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The contemporary monitoring of cerebrovascular reactivity (CVR) relies on invasive intracranial pressure (ICP) monitoring which limits its application. Interest is shifting towards near-infrared spectroscopic regional cerebral oxygen saturation (rSO2)-based indices of CVR which are less invasive and have improved spatial resolution. This study aims to examine and model the relationship between ICP and rSO2-based indices of CVR. Through a retrospective cohort study of prospectively collected physiologic data in moderate to severe traumatic brain injury (TBI) patients, linear mixed effects modeling techniques, augmented with time-series analysis, were utilized to evaluate the ability of rSO2-based indices of CVR to model ICP-based indices. It was found that rSO2-based indices of CVR had a statistically significant linear relationship with ICP-based indices, even when the hierarchical and autocorrelative nature of the data was accounted for. This strengthens the body of literature indicating the validity of rSO2-based indices of CVR and potential greatly expands the scope of CVR monitoring.
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Pressão Intracraniana , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Estudos Retrospectivos , Projetos de Pesquisa , TecnologiaRESUMO
The modeling and forecasting of cerebral pressure-flow dynamics in the time-frequency domain have promising implications for veterinary and human life sciences research, enhancing clinical care by predicting cerebral blood flow (CBF)/perfusion, nutrient delivery, and intracranial pressure (ICP)/compliance behavior in advance. Despite its potential, the literature lacks coherence regarding the optimal model type, structure, data streams, and performance. This systematic scoping review comprehensively examines the current landscape of cerebral physiological time-series modeling and forecasting. It focuses on temporally resolved cerebral pressure-flow and oxygen delivery data streams obtained from invasive/non-invasive cerebral sensors. A thorough search of databases identified 88 studies for evaluation, covering diverse cerebral physiologic signals from healthy volunteers, patients with various conditions, and animal subjects. Methodologies range from traditional statistical time-series analysis to innovative machine learning algorithms. A total of 30 studies in healthy cohorts and 23 studies in patient cohorts with traumatic brain injury (TBI) concentrated on modeling CBFv and predicting ICP, respectively. Animal studies exclusively analyzed CBF/CBFv. Of the 88 studies, 65 predominantly used traditional statistical time-series analysis, with transfer function analysis (TFA), wavelet analysis, and autoregressive (AR) models being prominent. Among machine learning algorithms, support vector machine (SVM) was widely utilized, and decision trees showed promise, especially in ICP prediction. Nonlinear models and multi-input models were prevalent, emphasizing the significance of multivariate modeling and forecasting. This review clarifies knowledge gaps and sets the stage for future research to advance cerebral physiologic signal analysis, benefiting neurocritical care applications.
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Lesões Encefálicas Traumáticas , Animais , HumanosRESUMO
Impedance spectroscopy is a powerful characterization method to evaluate the performance of electrochemical systems. However, overlapping signals in the resulting impedance spectra oftentimes cause misinterpretation of the data. The distribution of relaxation times (DRT) method overcomes this problem by transferring the impedance data from the frequency domain into the time domain, which yields DRT spectra with an increased resolution. Unfortunately, the determination of the DRT is an ill-posed problem, and appropriate mathematical regularizations become inevitable to find suitable solutions. The Tikhonov algorithm is a widespread method for computing DRT data, but it leads to unlikely spectra due to necessary boundaries. Therefore, we introduce the application of three alternative algorithms (Gold, Richardson Lucy, Sparse Spike) for the determination of stable DRT solutions and compare their performances. As the promising Sparse Spike deconvolution has a limited scope when using one single regularization parameter, we furthermore replaced the scalar regularization parameter with a vector. The resulting method is able to calculate well-resolved DRT spectra.
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Algoritmos , Impedância ElétricaRESUMO
BACKGROUND: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. METHODS: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score. RESULTS: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009). CONCLUSION: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.
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Cetuximab/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Platina/administração & dosagem , Platina/efeitos adversos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
PURPOSE: To test whether the oxygen uptake ([Formula: see text]) plateau at [Formula: see text] is simply a calculation artifact caused by the variability of [Formula: see text] or a clearly identifiable physiological event. METHODS: Forty-six male participants performed an incremental ramp and a [Formula: see text] verification test. Variability of the difference between adjacent sampling intervals (difference) and of the slope of the [Formula: see text]-workload relationship (slope) in the submaximal intensity domain were calculated. Workload defined sampling intervals used for the calculation of the difference and slope were systematically increased from 20 to 100 W until the expected risk of false plateau diagnoses based on the Gaussian distribution function was lower than 5%. Overall, more than 1500 differences and slopes were analyzed. Subsequently, frequencies of plateau diagnoses in the submaximal and maximal intensity domains were compared. RESULTS: Variability of the difference and slope decreased with increasing sampling interval (p < 0.001). At a sampling interval of 50 W, the predefined acceptable risk of false plateau diagnoses (≤ 5%) was achieved. At this sampling interval, the actual frequency (1.4%) of false-positive plateau diagnoses did not differ from the expected frequency in the submaximal intensity domain (1.6%; p = 0.491). In contrast, the actual frequency at maximal intensity (35.7%) was significantly higher compared to the submaximal intensity domain (p < 0.001) and even higher than the expected frequency of false-positive diagnoses (p < 0.001). CONCLUSION: The [Formula: see text] plateau at [Formula: see text] represents a physiological event and no calculation artifact caused by [Formula: see text] variability. However, detecting a [Formula: see text] plateau with sufficient certainty requires large sampling intervals.
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Artefatos , Teste de Esforço/métodos , Consumo de Oxigênio , Condicionamento Físico Humano/métodos , Adulto , Variação Biológica da População , Teste de Esforço/normas , Humanos , Masculino , Condicionamento Físico Humano/normasRESUMO
Quantitative peptide-binding motifs of MHC class I alleles provide a valuable tool to efficiently identify putative T cell epitopes. Detailed information on equine MHC class I alleles is still very limited, and to date, only a single equine MHC class I allele, Eqca-1*00101 (ELA-A3 haplotype), has been characterized. The present study extends the number of characterized ELA class I specificities in two additional haplotypes found commonly in the Thoroughbred breed. Accordingly, we here report quantitative binding motifs for the ELA-A2 allele Eqca-16*00101 and the ELA-A9 allele Eqca-1*00201. Utilizing analyses of endogenously bound and eluted ligands and the screening of positional scanning combinatorial libraries, detailed and quantitative peptide-binding motifs were derived for both alleles. Eqca-16*00101 preferentially binds peptides with aliphatic/hydrophobic residues in position 2 and at the C-terminus, and Eqca-1*00201 has a preference for peptides with arginine in position 2 and hydrophobic/aliphatic residues at the C-terminus. Interestingly, the Eqca-16*00101 motif resembles that of the human HLA A02-supertype, while the Eqca-1*00201 motif resembles that of the HLA B27-supertype and two macaque class I alleles. It is expected that the identified motifs will facilitate the selection of candidate epitopes for the study of immune responses in horses.
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Epitopos de Linfócito T/imunologia , Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I/metabolismo , Fragmentos de Peptídeos/metabolismo , Motivos de Aminoácidos , Animais , Haplótipos , Antígenos de Histocompatibilidade Classe I/imunologia , Cavalos , Fragmentos de Peptídeos/imunologia , Ligação Proteica , Domínios ProteicosRESUMO
Here we describe a detailed quantitative peptide-binding motif for the common equine leukocyte antigen (ELA) class I allele Eqca-1*00101, present in roughly 25 % of Thoroughbred horses. We determined a preliminary binding motif by sequencing endogenously bound ligands. Subsequently, a positional scanning combinatorial library (PSCL) was used to further characterize binding specificity and derive a quantitative motif involving aspartic acid in position 2 and hydrophobic residues at the C-terminus. Using this motif, we selected and tested 9- and 10-mer peptides derived from the equine herpesvirus type 1 (EHV-1) proteome for their capacity to bind Eqca-1*00101. PSCL predictions were very efficient, with an receiver operating characteristic (ROC) curve performance of 0.877, and 87 peptides derived from 40 different EHV-1 proteins were identified with affinities of 500 nM or higher. Quantitative analysis revealed that Eqca-1*00101 has a narrow peptide-binding repertoire, in comparison to those of most human, non-human primate, and mouse class I alleles. Peripheral blood mononuclear cells from six EHV-1-infected, or vaccinated but uninfected, Eqca-1*00101-positive horses were used in IFN-γ enzyme-linked immunospot (ELISPOT) assays. When we screened the 87 Eqca-1*00101-binding peptides for T cell reactivity, only one Eqca-1*00101 epitope, derived from the intermediate-early protein ICP4, was identified. Thus, despite its common occurrence in several horse breeds, Eqca-1*00101 is associated with a narrow binding repertoire and a similarly narrow T cell response to an important equine viral pathogen. Intriguingly, these features are shared with other human and macaque major histocompatibility complex (MHC) molecules with a similar specificity for D in position 2 or 3 in their main anchor motif.
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Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Herpesvirus Equídeo 1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Linfócitos T Citotóxicos/imunologia , Alelos , Animais , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Infecções por Herpesviridae/virologia , Herpesvirus Equídeo 1/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Humanos , Leucócitos Mononucleares , Camundongos , Ligação Proteica , Proteoma/imunologia , Linfócitos T Citotóxicos/metabolismo , Espectrometria de Massas em TandemRESUMO
Cerebrovascular pressure reactivity plays a key role in maintaining constant cerebral blood flow. Unfortunately, this mechanism is often impaired in acute traumatic neural injury states, exposing the already injured brain to further pressure-passive insults. While there has been much work on the association between impaired cerebrovascular reactivity following moderate/severe traumatic brain injury (TBI) and worse long-term outcomes, there is yet to be a comprehensive review on the association between cerebrovascular pressure reactivity and intracranial pressure (ICP) extremes. Therefore, we conducted a systematic review of the literature for all studies presenting a quantifiable statistical association between a continuous measure of cerebrovascular pressure reactivity and ICP in a human TBI cohort. The methodology described in the Cochrane Handbook for Systematic Reviews was used. BIOSIS, Cochrane Library, EMBASE, Global Health, MEDLINE, and SCOPUS were all searched from their inceptions to March of 2023 for relevant articles. Full-length original works with a sample size of ≥10 patients with moderate/severe TBI were included in this review. Data were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A total of 16 articles were included in this review. Studies varied in population characteristics and statistical tests used. Five studies looked at transcranial Doppler-based indices and 13 looked at ICP-based indices. All but two studies were able to present a statistically significant association between cerebrovascular pressure reactivity and ICP. Based on the findings of this review, impaired reactivity seems to be associated with elevated ICP and reduced ICP waveform complexity. This relationship may allow for the calculation of patient-specific ICP thresholds, past which cerebrovascular reactivity becomes persistently deranged. However, further work is required to better understand this relationship and improve algorithmic derivation of such individualized ICP thresholds.
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Traumatic brain injury (TBI) poses a significant global public health challenge necessitating a profound understanding of cerebral physiology. The dynamic nature of TBI demands sophisticated methodologies for modeling and predicting cerebral signals to unravel intricate pathophysiology and predict secondary injury mechanisms prior to their occurrence. In this comprehensive scoping review, we focus specifically on multivariate cerebral physiologic signal analysis in the context of multi-modal monitoring (MMM) in TBI, exploring a range of techniques including multivariate statistical time-series models and machine learning algorithms. Conducting a comprehensive search across databases yielded 7 studies for evaluation, encompassing diverse cerebral physiologic signals and parameters from TBI patients. Among these, five studies concentrated on modeling cerebral physiologic signals using statistical time-series models, while the remaining two studies primarily delved into intracranial pressure (ICP) prediction through machine learning models. Autoregressive models were predominantly utilized in the modeling studies. In the context of prediction studies, logistic regression and Gaussian processes (GP) emerged as the predominant choice in both research endeavors, with their performance being evaluated against each other in one study and other models such as random forest, and decision tree in the other study. Notably among these models, random forest model, an ensemble learning approach, demonstrated superior performance across various metrics. Additionally, a notable gap was identified concerning the absence of studies focusing on prediction for multivariate outcomes. This review addresses existing knowledge gaps and sets the stage for future research in advancing cerebral physiologic signal analysis for neurocritical care improvement.
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Lesões Encefálicas Traumáticas , Aprendizado de Máquina , Humanos , Lesões Encefálicas Traumáticas/fisiopatologia , Análise Multivariada , Encéfalo/fisiopatologia , Processamento de Sinais Assistido por ComputadorRESUMO
Objective.Continuous monitoring of cerebrospinal compliance (CC)/cerebrospinal compensatory reserve (CCR) is crucial for timely interventions and preventing more substantial deterioration in the context of acute neural injury, as it enables the early detection of abnormalities in intracranial pressure (ICP). However, to date, the literature on continuous CC/CCR monitoring is scattered and occasionally challenging to consolidate.Approach.We subsequently conducted a systematic scoping review of the human literature to highlight the available continuous CC/CCR monitoring methods.Main results.This systematic review incorporated a total number of 76 studies, covering diverse patient types and focusing on three primary continuous CC or CCR monitoring metrics and methods-Moving Pearson's correlation between ICP pulse amplitude waveform and ICP, referred to as RAP, the Spiegelberg Compliance Monitor, changes in cerebral blood flow velocity with respect to the alternation of ICP measured through transcranial doppler (TCD), changes in centroid metric, high frequency centroid (HFC) or higher harmonics centroid (HHC), and the P2/P1 ratio which are the distinct peaks of ICP pulse wave. The majority of the studies in this review encompassed RAP metric analysis (n= 43), followed by Spiegelberg Compliance Monitor (n= 11), TCD studies (n= 9), studies on the HFC/HHC (n= 5), and studies on the P2/P1 ratio studies (n= 6). These studies predominantly involved acute traumatic neural injury (i.e. Traumatic Brain Injury) patients and those with hydrocephalus. RAP is the most extensively studied of the five focused methods and exhibits diverse applications. However, most papers lack clarification on its clinical applicability, a circumstance that is similarly observed for the other methods.Significance.Future directions involve exploring RAP patterns and identifying characteristics and artifacts, investigating neuroimaging correlations with continuous CC/CCR and integrating machine learning, holding promise for simplifying CC/CCR determination. These approaches should aim to enhance the precision and accuracy of the metric, making it applicable in clinical practice.
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Pressão Intracraniana , Humanos , Monitorização Fisiológica/métodos , Pressão Intracraniana/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Complacência (Medida de Distensibilidade)RESUMO
Near-infrared spectroscopy (NIRS) regional cerebral oxygen saturation (rSO2)-based cerebrovascular reactivity (CVR) monitoring has enabled entirely non-invasive, continuous monitoring during both acute and long-term phases of care. To date, long-term post-injury CVR has not been properly characterized after acute traumatic neural injury, also known as traumatic brain injury (TBI). This study aims to compare CVR in those recovering from moderate-to-severe TBI with a healthy control group. A total of 101 heathy subjects were recruited for this study, along with 29 TBI patients. In the healthy cohort, the arterial blood pressure variant of the cerebral oxygen index (COx_a) was not statistically different between males and females or in the dominant and non-dominant hemispheres. In the TBI cohort, COx_a was not statistically different between the first and last available follow-up or by the side of cranial surgery. Surprisingly, CVR, as measured by COx_a, was statistically better in those recovering from TBI than those in the healthy cohort. In this prospective cohort study, CVR, as measured by NIRS-based methods, was found to be more active in those recovering from TBI than in the healthy cohort. This study may indicate that in individuals that survive TBI, CVR may be enhanced as a neuroprotective measure.
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BACKGROUND: Optimal cerebral perfusion pressure (CPPopt) has emerged as a promising personalized medicine approach to the management of moderate-to-severe traumatic brain injury (TBI). Though literature demonstrating its association with poor outcomes exists, there is yet to be work done on its association with outcome transition due to a lack of serial outcome data analysis. In this study we investigate the association between various metrics of CPPopt and failure to improve in outcome over time. METHODS: CPPopt was derived using three different cerebrovascular reactivity indices; the pressure reactivity index (PRx), the pulse amplitude index (PAx), and the RAC index. For each index, % times spent with cerebral perfusion pressure (CPP) above and below its CPPopt and upper and lower limits of reactivity were calculated. Patients were dichotomized based on improvement in Glasgow Outcome Scale-Extended (GOSE) scores into Improved vs. Not Improved between 1 and 3 months, 3 and 6 months, and 1- and 6-month post-TBI. Logistic regression analyses were then conducted, adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. RESULTS: This study included a total of 103 patients from the Winnipeg Acute TBI Database. Through Mann-Whitney U testing and logistic regression analysis, it was found that % time spent with CPP below CPPopt was associated with failure to improve in outcome, while % time spent with CPP above CPPopt was generally associated with improvement in outcome. CONCLUSIONS: Our study supports the existing narrative that time spent with CPP below CPPopt results in poorer outcomes. However, it also suggests that time spent above CPPopt may not be associated with worse outcomes and is possibly even associated with improvement in outcome.
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Regional cerebral oxygen saturation (rSO2), a method of cerebral tissue oxygenation measurement, is recorded using non-invasive near-infrared Spectroscopy (NIRS) devices. A major limitation is that recorded signals often contain artifacts. Manually removing these artifacts is both resource and time consuming. The objective was to evaluate the applicability of using wavelet analysis as an automated method for simple signal loss artifact clearance of rSO2 signals obtained from commercially available devices. A retrospective observational study using existing populations (healthy control (HC), elective spinal surgery patients (SP), and traumatic brain injury patients (TBI)) was conducted. Arterial blood pressure (ABP) and rSO2 data were collected in all patients. Wavelet analysis was determined to be successful in removing simple signal loss artifacts using wavelet coefficients and coherence to detect signal loss artifacts in rSO2 signals. The removal success rates in HC, SP, and TBI populations were 100%, 99.8%, and 99.7%, respectively (though it had limited precision in determining the exact point in time). Thus, wavelet analysis may prove to be useful in a layered approach NIRS signal artifact tool utilizing higher-frequency data; however, future work is needed.
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Stellate cells are principal neurons in the entorhinal cortex that contribute to spatial processing. They also play a role in the context of Alzheimer's disease as they accumulate Amyloid beta early in the disease. Producing human stellate cells from pluripotent stem cells would allow researchers to study early mechanisms of Alzheimer's disease, however, no protocols currently exist for producing such cells. In order to develop novel stem cell protocols, we characterize at high resolution the development of the porcine medial entorhinal cortex by tracing neuronal and glial subtypes from mid-gestation to the adult brain to identify the transcriptomic profile of progenitor and adult stellate cells. Importantly, we could confirm the robustness of our data by extracting developmental factors from the identified intermediate stellate cell cluster and implemented these factors to generate putative intermediate stellate cells from human induced pluripotent stem cells. Six transcription factors identified from the stellate cell cluster including RUNX1T1, SOX5, FOXP1, MEF2C, TCF4, EYA2 were overexpressed using a forward programming approach to produce neurons expressing a unique combination of RELN, SATB2, LEF1 and BCL11B observed in stellate cells. Further analyses of the individual transcription factors led to the discovery that FOXP1 is critical in the reprogramming process and omission of RUNX1T1 and EYA2 enhances neuron conversion. Our findings contribute not only to the profiling of cell types within the developing and adult brain's medial entorhinal cortex but also provides proof-of-concept for using scRNAseq data to produce entorhinal intermediate stellate cells from human pluripotent stem cells in-vitro.
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Equine influenza (EI) is a highly contagious acute respiratory disease of equines that is caused mainly by the H3N8 subtype of influenza A virus. Vaccinating horses against EI is the most effective strategy to prevent the infection. The current study aimed to compare the kinetics of EI-specific humoral- and cell-mediated immunity (CMI) in horses receiving either identical or mixed vaccinations. Two groups of horses were previously (six months prior) vaccinated with either Calvenza 03 EIV EHV® (G1) or Fluvac Innovator® (G2) vaccine. Subsequently, both groups received a booster single dose of Calvenza 03 EIV EHV®. Immune responses were assessed after 10 weeks using single radial hemolysis (SRH), virus neutralization (VN), and EliSpot assays. Our results revealed that Calvenza-03 EIV/EHV®-immunized horses had significantly higher protective EI-specific SRH antibodies and VN antibodies. Booster immunization with Calvenza-03 EIV/EHV® vaccine significantly stimulated cell-mediated immune response as evidenced by significant increase in interferon-γ-secreting peripheral blood mononuclear cells. In conclusion, Calvenza-03 EIV/EHV® vaccine can be safely and effectively used for booster immunization to elicit optimal long persisting humoral and CMI responses even if the horses were previously immunized with a heterogeneous vaccine.
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The entorhinal cortex (EC) is the spatial processing center of the brain and structurally is an interface between the three layered paleocortex and six layered neocortex, known as the periarchicortex. Limited studies indicate peculiarities in the formation of the EC such as early emergence of cells in layers (L) II and late deposition of LIII, as well as divergence in the timing of maturation of cell types in the superficial layers. In this study, we examine developmental events in the entorhinal cortex using an understudied model in neuroanatomy and development, the pig and supplement the research with BrdU labeling in the developing mouse EC. We determine the pig serves as an excellent anatomical model for studying human neurogenesis, given its long gestational length, presence of a moderate sized outer subventricular zone and early cessation of neurogenesis during gestation. Immunohistochemistry identified prominent clusters of OLIG2+ oligoprogenitor-like cells in the superficial layers of the lateral EC (LEC) that are sparser in the medial EC (MEC). These are first detected in the subplate during the early second trimester. MRI analyses reveal an acceleration of EC growth at the end of the second trimester. BrdU labeling of the developing MEC, shows the deeper layers form first and prior to the superficial layers, but the LV/VI emerges in parallel and the LII/III emerges later, but also in parallel. We coin this lamination pattern parallel lamination. The early born Reln+ stellate cells in the superficial layers express the classic LV marker, Bcl11b (Ctip2) and arise from a common progenitor that forms the late deep layer LV neurons. In summary, we characterize the developing EC in a novel animal model and outline in detail the formation of the EC. We further provide insight into how the periarchicortex forms in the brain, which differs remarkably to the inside-out lamination of the neocortex.
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Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27-0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33-0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.
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To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.
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Células/classificação , Neocórtex/citologia , Transcriptoma , Animais , Biologia Computacional , Humanos , Neuroglia/classificação , Neurônios/classificação , Análise de Célula Única , Terminologia como AssuntoRESUMO
Molecular spectra calculated with quantum-chemical methods are subject to a number of uncertainties (e.g., errors introduced by the computational methodology) that hamper the direct comparison of experiment and computation. Judging these uncertainties is crucial for drawing reliable conclusions from the interplay of experimental and theoretical spectroscopy, but largely relies on subjective judgment. Here, we explore the application of methods from uncertainty quantification to theoretical spectroscopy, with the ultimate goal of providing systematic error bars for calculated spectra. As a first target, we consider distortions of the underlying molecular structure as one important source of uncertainty. We show that by performing a principal component analysis, the most influential collective distortions can be identified, which allows for the construction of surrogate models that are amenable to a statistical analysis of the propagation of uncertainties in the molecular structure to uncertainties in the calculated spectrum. This is applied to the calculation of X-ray emission spectra of iron carbonyl complexes, of the electronic excitation spectrum of a coumarin dye, and of the infrared spectrum of alanine. We show that with our approach it becomes possible to obtain error bars for calculated spectra that account for uncertainties in the molecular structure. This is an important first step towards systematically quantifying other relevant sources of uncertainty in theoretical spectroscopy.
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PURPOSE: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.Experimental Design: We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. RESULTS: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. CONCLUSIONS: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.