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Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here, in experiments on rats and mice, we show that the peripheral afferent nociceptive information undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics, we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG. Filtering induced by focal application of GABA or optogenetic GABA release from the DRG-transplanted GABAergic progenitor cells was specific to nociceptive fibers. Light-sheet imaging and computer modeling demonstrated that, compared to other somatosensory fiber types, nociceptors have shorter stem axons, making somatic control over t-junctional filtering more efficient. Optogenetically induced GABA release within DRG from the transplanted GABAergic cells enhanced filtering and alleviated hypersensitivity to noxious stimulation produced by chronic inflammation and neuropathic injury in vivo. These findings support "gating" of pain information by DRGs and suggest new therapeutic approaches for pain relief.
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Gânglios Espinais , Nociceptividade , Ratos , Camundongos , Animais , Ratos Sprague-Dawley , Gânglios Espinais/fisiologia , Sistema Nervoso Central , Dor , Ácido gama-AminobutíricoRESUMO
Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity. We interrogated a longitudinal collection of 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors and were subsequently treated with endocrine therapy (ET) by means of highly sensitive and affordable digital PCR and SafeSEQ sequencing. Baseline PIK3CA and TP53 mutations were prognostic of a shorter progression-free survival in our population. Mutant PIK3CA was prognostic in the subset of patients receiving fulvestrant monotherapy after progression to a CDK4/6 inhibitor (CDK4/6i)-containing regimen, and its suppression was predictive in a case of long-term benefit with alpelisib. Mutant ESR1 was prognostic in patients who did not receive concurrent CDK4/6i, an impact influenced by the variant allele frequency, and its early suppression was strongly predictive of efficacy and associated with long-term benefit in the whole cohort. Mutations in ESR1, TP53, and KRAS emerged as putative drivers of acquired resistance. These findings collectively contribute to the characterization of longitudinal ctDNA in real-world cases of HR+/HER2- mBC previously exposed to aromatase inhibitors and support ongoing studies either targeting actionable alterations or leveraging the ultra-sensitive tracking of ctDNA.
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Inibidores da Aromatase , Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Biópsia Líquida , Fosfatidilinositol 3-Quinases , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , MutaçãoRESUMO
BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC. METHODS: Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, [Formula: see text] 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response. DISCUSSION: A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100 .
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Ácidos Nucleicos Livres/sangue , DNA Viral/sangue , Monitoramento de Medicamentos/métodos , Neoplasias Orofaríngeas/tratamento farmacológico , Papillomaviridae/genética , Infecções por Papillomavirus/sangue , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Carboplatina/administração & dosagem , Quimiorradioterapia , Cisplatino/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/sangue , Neoplasias Orofaríngeas/virologia , Paclitaxel/administração & dosagem , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Chronic kidney disease (CKD) is a major public health issue in the USA. Identification of monogenic causes of CKD, which are present in â¼10% of adult cases, can impact prognosis and patient management. Broad gene panels can provide unbiased testing approaches, which are advantageous in phenotypically heterogeneous diseases. However, the use and yield of broad genetic panels by nephrologists in clinical practice is not yet well characterized. METHODS: Renal genetic testing, ordered exclusively for clinical purposes, predominantly by general and transplant nephrologists within the USA, was performed on 1,007 consecutive unique patient samples. Testing was performed using a commercially available next-generation sequencing-based 382 gene kidney disease panel. Pathogenic (P) and likely pathogenic (LP) variants were reported. Positive findings included a monoallelic P/LP variant in an autosomal dominant or X-linked gene and biallelic P/LP variants in autosomal recessive genes. RESULTS: Positive genetic findings were identified in 21.1% (212/1,007) of cases. A total of 220 positive results were identified across 48 genes. Positive results occurred most frequently in the PKD1 (34.1%), COL4A5 (10.9%), PKD2 (10.0%), COL4A4 (6.4%), COL4A3 (5.9%), and TTR (4.1%) genes. Variants identified in the remaining 42 genes comprised 28.6% of the total positive findings, including single positive results in 26 genes. Positive results in >1 gene were identified in 7.5% (16/212) of cases. CONCLUSIONS: Use of broad panel genetic testing by clinical nephrologists had a high success rate, similar to results obtained by academic centers specializing in genetics.
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Rim , Insuficiência Renal Crônica , Adulto , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genéticaRESUMO
KEY POINTS: Rat somatosensory neurons express a junctional protein, junctophilin-4 (JPH4) JPH4 is necessary for the formation of store operated Ca2+ entry (SOCE) complex at the junctions between plasma membrane and endoplasmic reticulum in these neurons. Knockdown of JPH4 impairs endoplasmic reticulum Ca2+ store refill and junctional Ca2+ signalling in sensory neurons. In vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly attenuated experimentally induced inflammatory pain in rats. Junctional nanodomain Ca2+ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms. ABSTRACT: Junctions of endoplasmic reticulum and plasma membrane (ER-PM junctions) form signalling nanodomains in eukaryotic cells. ER-PM junctions are present in peripheral sensory neurons and are important for the fidelity of G protein coupled receptor (GPCR) signalling. Yet little is known about the assembly, maintenance and physiological role of these junctions in somatosensory transduction. Using fluorescence imaging, proximity ligation, super-resolution microscopy, in vitro and in vivo gene knockdown we demonstrate that a member of the junctophilin protein family, junctophilin-4 (JPH4), is necessary for the formation of store operated Ca2+ entry (SOCE) complex at the ER-PM junctions in rat somatosensory neurons. Thus we show that JPH4 localises to the ER-PM junctional areas and co-clusters with SOCE proteins STIM1 and Orai1 upon ER Ca2+ store depletion. Knockdown of JPH4 impairs SOCE and ER Ca2+ store refill in sensory neurons. Furthermore, we demonstrate a key role of the JPH4 and junctional nanodomain Ca2+ signalling in the pain-like response induced by the inflammatory mediator bradykinin. Indeed, an in vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly shortened the duration of nocifensive behaviour induced by hindpaw injection of bradykinin in rats. Since the ER supplies Ca2+ for the excitatory action of multiple inflammatory mediators, we suggest that junctional nanodomain Ca2+ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.
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Sinalização do Cálcio , Cálcio , Animais , Cálcio/metabolismo , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana , Proteína ORAI1 , Ratos , Células Receptoras Sensoriais/metabolismo , Molécula 1 de Interação Estromal/metabolismoRESUMO
Kv7.1-Kv7.5 (KCNQ1-5) K+ channels are voltage-gated K+ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K+ currents, such as neuronal M current and cardiac IKs. Specific biophysical properties of Kv7 channels make them particularly well placed to control the activity of excitable cells. Indeed, these channels often work as 'excitability breaks' and are targeted by various hormones and modulators to regulate cellular activity outputs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, arrhythmias, deafness and some others. Not surprisingly, this channel family attracts considerable attention as potential drug targets. Here we will review biophysical properties and tissue expression profile of Kv7 channels, discuss recent advances in the understanding of their structure as well as their role in various neurological, cardiovascular and other diseases and pathologies. We will also consider a scope for therapeutic targeting of Kv7 channels for treatment of the above health conditions.
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Epilepsia , Transtornos Mentais , Humanos , Canais de Potássio KCNQ/genética , NeurôniosRESUMO
BACKGROUND: The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. METHODS: Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched-chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc-finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). RESULTS: The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%-69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%-36.6%; P < .001). The sensitivity for resectable recurrence (n = 20) was also higher (ctDNA, 60.0%; CEA, 20.0%; P = .01). The specificity did not differ between the tests (ctDNA, 97.9%; 95% CI, 93.2%-99.6%; CEA, 96.4%; 95% CI, 91.4%-99.0%). When adjustments were made for other predictors of the presence of recurrence, a positive ctDNA test was an independent predictor (odds ratio, 155.7; 95% CI, 17.9-1360.6; P < .001), whereas CEA was not (odds ratio, 2.5; 95% CI, 0.3-20.6; P = .407). CONCLUSIONS: The quantitative ctDNA test showed superior sensitivity in comparison with CEA without a difference in the specificity for detecting recurrent CRC. Longitudinal studies are warranted to further assess the utility (specifically the survival benefit) of methylated BCAT1/IKZF1 ctDNA in the surveillance of patients with CRC.
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Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/análise , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/sangue , Epigênese Genética , Feminino , Humanos , Fator de Transcrição Ikaros/sangue , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Transaminases/sangueRESUMO
Aim: To determine the concordance between plasma and tissue RAS mutation status in metastatic colorectal cancer patients to gauge whether blood-based testing is a viable alternative. We also evaluated the change in mutation status on progression. Materials/methods: RAS testing was performed on plasma from patients commencing first-line therapy (OncoBEAM™ RAS CEIVD kit). Results were then compared with formalin-fixed paraffin embedded tumor samples. Results: The overall percentage agreement (concordance) was 86.0% (86/100), which demonstrates that blood-based testing is an alternative to tissue-based testing. Reproducibility was 100% between three laboratories and 20% showed changes in their RAS mutational status on progression. Conclusion: These results show good concordance between tissue and plasma samples and suggest the need for longitudinal plasma testing during treatment to guide management decisions.
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Biomarcadores Tumorais , Genes ras , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , DNA Tumoral Circulante , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Progressão da Doença , Feminino , Humanos , Biópsia Líquida/métodos , Biópsia Líquida/normas , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/terapia , Tempo para o TratamentoAssuntos
Fraturas do Quadril , Humanos , Fraturas do Quadril/cirurgia , Coluna Vertebral , IncidênciaAssuntos
Anestesia por Condução , Anestesia Geral , Delírio , Fraturas do Quadril , Idoso , Anestesia por Condução/efeitos adversos , Anestesia Geral/efeitos adversos , Delírio/epidemiologia , Delírio/etiologia , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/cirurgia , Humanos , Incidência , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.
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Inibidor da Ligação a Diazepam , Gânglios Espinais , Neuroglia , Animais , Gânglios Espinais/metabolismo , Neuroglia/metabolismo , Camundongos , Ratos , Humanos , Inibidor da Ligação a Diazepam/metabolismo , Inibidor da Ligação a Diazepam/genética , Masculino , Células Receptoras Sensoriais/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genética , Hiperalgesia/metabolismo , Hiperalgesia/genética , Hiperalgesia/patologia , Ratos Sprague-Dawley , Mecanotransdução Celular , Camundongos Endogâmicos C57BLRESUMO
BLOODPAC is a public-private consortium that develops best practices, coordinates clinical and translational research, and manages the BLOODPAC Data Commons to broadly support the liquid biopsy community and accelerate regulatory review to aid patient accessibility. BLOODPAC previously recommended 11 preanalytical minimal technical data elements (MTDEs) for BLOODPAC-sponsored studies and data submitted to BLOODPAC Data Commons. The current landscape analysis evaluates the overlap of the BLOODPAC MTDEs with current best practices, guidelines, and standards documents related to clinical and research liquid biopsy applications. Our findings indicate an existing high degree of concordance among these documents. Where differences exist, the BLOODPAC preanalytical MTDEs can be considered a minimal practicable set for organizations to utilize. These MTDEs were developed following extensive examination of best practices and iterative conversations with the U.S. FDA. BLOODPAC recommends the use of these MTDEs in submissions to data commons and to support liquid biopsy clinical trials and research globally.
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Importance: Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus-positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity. Objective: To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC. Design, Setting, and Participants: This phase 2 nonrandomized controlled trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023. Interventions: Addition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV. Main Outcomes and Measures: Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated. Results: The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS. Conclusions and Relevance: This phase 2 nonrandomized controlled trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection. Trial Registration: ClinicalTrials.gov Identifier: NCT03107182.
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Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadjuvante , Nivolumabe , Neoplasias Orofaríngeas , Humanos , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Infecções por Papillomavirus/complicações , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
Neuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca2+-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD). We found that precluding Ca2+ binding to the EF3 hand, but not to EF1, EF2, or EF4 hands, abolishes oxidation-induced enhancement of KV7.4 currents. Monitoring FRET (Fluorescence Resonance Energy Transfer) between helices A and B using purified CRDs tagged with fluorescent proteins, we observed that S2S3 peptides cause a reversal of the signal in the presence of Ca2+ but have no effect in the absence of this cation or if the peptide is oxidized. The capacity of loading EF3 with Ca2+ is essential for this reversal of the FRET signal, whereas the consequences of obliterating Ca2+ binding to EF1, EF2, or EF4 are negligible. Furthermore, we show that EF3 is critical for translating Ca2+ signals to reorient the AB fork. Our data are consistent with the proposal that oxidation of cysteine residues in the S2S3 loop relieves KV7 channels from a constitutive inhibition imposed by interactions between the EF3 hand of CaM which is crucial for this signaling.
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Calmodulina , Canais de Potássio , Transdução de Sinais , Cálcio/metabolismo , Calmodulina/metabolismo , Oxirredução , Estrutura Secundária de Proteína , Canais de Potássio/metabolismoRESUMO
BACKGROUND: Loneliness during adolescence has adverse consequences for mental health, education and employment outcomes. Yet, we know little about common correlates of loneliness among adolescents, making intervention work difficult. AIMS: In this study, we (1) explore individual-, school- and country-level correlates of loneliness to help identify potential intervention targets, and (2) examine the influence of loneliness on academic performance. SAMPLE: A total of 518,210 students aged 15 years from 75 countries provided self-reported loneliness data. RESULTS: Using multilevel modelling, we found individual-, school- and country-level correlates of self-reported school-based loneliness, and showed that loneliness negatively influenced academic performance. CONCLUSIONS: Based on the findings, interventions that focus on enhancing social and emotional skills, increasing trust between teachers and students and changing school climate to be more inclusive are likely to be the most effective for adolescents; they should also be culturally sensitive.
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Desempenho Acadêmico , Pessoal de Educação , Humanos , Adolescente , Solidão , Instituições Acadêmicas , Estudantes/psicologiaRESUMO
We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly and specifically expressed in satellite glia cells (SGCs) of mice, rat and human, but not in sensory neurons or other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without significant effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as a partial agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly effecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons and these are also more enwrapped with DBI-expressing glia, as compared to other DRG neurons, suggesting a mechanism for specific effect of DBI on mechanosensation. These findings identified a new, peripheral neuron-glia communication mechanism modulating pain signalling, which can be targeted therapeutically.
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OBJECTIVES: The aim of this pilot study was to evaluate the presence of somatic mutations in matched tumor and circulating DNA (ctDNA) samples from patients with primary head and neck squamous cell carcinoma (HNSCC) and assess the association of changes in ctDNA levels with survival. MATERIALS AND METHODS: Our study included 62 patients with stage I-IVB HNSCC treated with surgery or radical chemoradiotherapy with curative intent. Plasma samples were obtained at baseline, at the end of treatment (EOT), and at disease progression. Tumor DNA was extracted from plasma (ctDNA) and tumor tissue (tDNA). The Safe Sequencing System was used assess the presence of pathogenic variants in four genes (TP53, CDKN2A, HRAS and PI3KCA) in both ctDNA and tDNA. RESULTS: Forty-five patients had available tissue and plasma samples. Concordance of genotyping results between tDNA and ctDNA at baseline was 53.3%. TP53 mutations were most commonly identified at baseline in both ctDNA (32.6%) and tDNA (40%). The presence of mutations in this restricted set of 4 genes in tissue samples at baseline was associated with decreased overall survival (OS) [median 58.3 months for patients with mutations vs. 89 months for patients without mutations, p < 0.013]. Similarly, patients presenting with mutations in ctDNA had shorter OS [median 53.8 vs. 78.6 months, p < 0.037]. CtDNA clearance at EOT did not show any association with PFS or OS. CONCLUSIONS: Liquid biopsy enables real-time molecular characterization of HNSCC and might predict survival. Larger studies are needed to validate the utility of ctDNA as a biomarker in HNSCC.
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Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Humanos , DNA Tumoral Circulante/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias Pulmonares/genética , Projetos Piloto , Mutação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Biomarcadores Tumorais/genéticaRESUMO
Molecular testing using blood-based liquid biopsy approaches has not been widely investigated in patients with glioma. A prospective single-center study enrolled patients with gliomas ranging from grade II to IV. Peripheral blood (PB) was drawn at different timepoints for circulating tumour DNA (ctDNA) monitoring. Next-generation sequencing (NGS) was used for the study of isocitrate dehydrogenase 1 (IDH1) mutations in the primary tumor. Beads, Emulsion, Amplification and Magnetics (BEAMing) was used for the study of IDH1 mutations in plasma and correlated with the NGS results in the tumor. Between February 2017 and July 2018, ten patients were enrolled, six with IDH1-mutant and four with IDH1 wild-type gliomas. Among the six IDH-mutant gliomas, three had the same IDH1 mutation detected in plasma (50%), and the IDH1-positive ctDNA result was obtained in patients either at diagnosis (no treatment) or during progressive disease. While the false-negative rate reached 86% (18/21), 15 out of the 18 (83%) plasma-negative results were from PB collected from the six IDH-mutant patients at times at which there was no accompanying evidence of tumor progression, as assessed by MRI. There were no false-positive cases in plasma collected from patients with IDH1 wild-type tumors. BEAMing detected IDH1 mutations in the plasma of patients with gliomas, with a modest clinical sensitivity (true positivity rate) but with 100% clinical specificity, with complete agreement between the mutant loci detected in tumor and plasma. Larger prospective studies should be conducted to expand on these findings, and further explore the clearance of mutations in PB from IDH1-positive patients in response to therapy.
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RATIONALE AND OBJECTIVES: The Radiology Scholars Certificate Program (RSCP) is an extracurricular program created for preclinical medical students to address disparities in radiology education and exposure during medical school. MATERIALS AND METHODS: The RSCP was designed as a year-long program for first- and second-year medical students. The 4 key components of the RSCP are: Exposure to radiology through shadowing, knowledge acquisition through self-paced case-based learning modules, knowledge application in interactive workshops, and completion of a scholarly project. Students are required to complete at least 3 hours of shadowing, attend at least 3 workshops, complete self-paced online modules, and complete a capstone project on a topic of their choosing. Pre- and post-program surveys were administered to assess trends in participants' perception of the field and imaging-related clinical knowledge. RESULTS: In the first year of the RSCP, 55% of the matriculating class enrolled and of those, 84% completed the program. Approximately half of participants were female. Participants demonstrated significant improvement in radiology knowledge, with average scores improving from 52.8% to 68.6% (p < .001) on the knowledge-related survey questions. Significant improvements were also observed in student-reported confidence with ordering and interpreting imaging studies and in their perceptions of the field. CONCLUSION: The RSCP is an effective tool for addressing deficits in radiology education and exposure during medical school. It is designed to be run by senior medical students under radiology resident and attending supervision. With motivated student and radiologist investment, the RSCP should be easily replicable in medical training programs worldwide.