Prevalence of EGFR Mutations in Patients With Resected Stages I to III NSCLC: Results From the EARLY-EGFR Study.

Introduction: There is limited literature on the prevalence of EGFR mutations in early stage NSCLC. EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early stage NSCLC.

Methods: This noninterventional, real-world study enrolled consecutive patients with resected stages IA to IIIB (American Joint Committee on Cancer eighth edition) NSCLC from 14 countries across Asia, Latin America, and the Middle East and Africa.

Extranodal natural killer/T cell lymphoma of the skeletal muscle.

This case report highlights a case of extranodal NK/T cell lymphoma initially misdiagnosed as myositis, emphasizing the appearance on both MRI and FDG PET images. The patient presented with systemic symptoms and calf muscle swelling, prompting imaging studies that revealed diffuse muscle involvement. Despite negative myositis markers and inconclusive biopsy, post-amputation findings confirmed lymphoma with EBV positivity.

Psychological Resilience Factors and Their Association With Weekly Stressor Reactivity During the COVID-19 Outbreak in Europe: Prospective Longitudinal Study.

Background: Cross-sectional relationships between psychosocial resilience factors (RFs) and resilience, operationalized as the outcome of low mental health reactivity to stressor exposure (low "stressor reactivity" [SR]), were reported during the first wave of the COVID-19 pandemic in 2020.

Objective: Extending these findings, we here examined prospective relationships and weekly dynamics between the same RFs and SR in a longitudinal sample during the aftermath of the first wave in several European countries.

Methods: Over 5 weeks of app-based assessments, participants reported weekly stressor exposure, mental health problems, RFs, and demographic data in 1 of 6 different languages.

The FeatureCloud Platform for Federated Learning in Biomedicine: Unified Approach.

Background: Machine learning and artificial intelligence have shown promising results in many areas and are driven by the increasing amount of available data. However, these data are often distributed across different institutions and cannot be easily shared owing to strict privacy regulations. Federated learning (FL) allows the training of distributed machine learning models without sharing sensitive data.

Determining the Correct Resection Level in Patients with Hirschsprung Disease Using Contrast Enema and Full Thickness Biopsies: Can the Diagnostic Accuracy be Improved by Examining Submucosal Nerve Fiber Thickness?

Background: Intraoperative resection level in patients with Hirschsprung disease (HD) is determined by contrast enema, surgeon's intraoperative judgement and full thickness biopsy (FTB) identifying ganglia. This study aims to evaluate diagnostic accuracy of contrast enema and FTB in determination of resection level and whether this can be improved by measuring submucosal nerve fiber diameter.

Methods: We retrospectively analyzed contrast enema and intraoperative FTBs obtained in our center, determining diagnostic accuracy for level of resection.

Pediatric Pleomorphic Adenoma of the Palate.

Pleomorphic adenoma is the most common salivary gland tumor but is extremely rare in pediatric patients. The parotid gland is the most affected salivary gland, and the minor salivary glands are rarely affected. Here, we report a case of a 12-year-old boy with a pleomorphic adenoma of the palate.

The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents.

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards.

Crh receptor priming in the bed nucleus of the stria terminalis (BNST) induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety.

The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear.

Dorsal raphé nucleus glucocorticoid receptors inhibit tph2 gene expression in male C57BL/6J mice.

The serotonergic dorsal raphé nucleus (DRN) expresses glucocorticoid receptors (GR), and systemic glucocorticoids have been shown to regulate expression and activity of tryptophan hydroxylase isoform 2, the rate-limiting enzyme for serotonin synthesis in brain. We have used intra-DRN injection of pseudotyped adeno-associated virus AAV2/9 transducing either green fluorescent protein (GFP control) or Cre recombinase (DRN GR deletion) in floxed GR mice to determine if DRN GR directly regulate DRN mRNA levels of tryptophan hydroxylase 2 (tph2). In a separate set of similarly-treated floxed GR mice, we also measured limbic forebrain region concentrations of serotonin (5-hydroxytryptamine; 5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA).

Acute Administration of the Nonpathogenic, Saprophytic Bacterium, Mycobacterium vaccae, Induces Activation of Serotonergic Neurons in the Dorsal Raphe Nucleus and Antidepressant-Like Behavior in Association with Mild Hypothermia.

Peripheral immune activation can have profound physiologic and behavioral effects. One mechanism through which immune activation may affect physiology and behavior is through actions on brainstem neuromodulatory systems, such as serotonergic systems. To test this hypothesis, in Experiment 1, adult male BALB/c mice were implanted with telemetric recording devices and then immunized with Mycobacterium vaccae NCTC 11659 (0.

Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice.

Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings.

Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice.

The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation.

Serotonergic systems in the balance: CRHR1 and CRHR2 differentially control stress-induced serotonin synthesis.

Anxiety and affective disorders are often associated with hypercortisolism and dysfunctional serotonergic systems, including increased expression of TPH2, the gene encoding the rate-limiting enzyme of neuronal serotonin synthesis. We previously reported that chronic glucocorticoid exposure is anxiogenic and increases rat Tph2 mRNA expression, but it was still unclear if this also translates to increased TPH2 protein levels and in vivo activity of the enzyme. Here, we found that adult male rats treated with corticosterone (CORT, 100 μg/ml) via the drinking water for 21 days indeed show increased TPH2 protein expression in the dorsal and ventral part of the dorsal raphe nucleus (DRD, DRV) during the light phase, abolishing the enzyme's diurnal rhythm.

Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis.

Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 μg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay.

Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary-adrenal axis response to restraint stress in adult male rats.

In rodents, the hypothalamo-pituitary-adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5α-reduction to the more potent androgen, dihydrotestosterone (DHT).

Sex differences in anxiety and emotional behavior.

Research has elucidated causal links between stress exposure and the development of anxiety disorders, but due to the limited use of female or sex-comparative animal models, little is known about the mechanisms underlying sex differences in those disorders. This is despite an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men, in addition to gender differences in severity and treatment efficacy. We here review human gender differences in generalized anxiety disorder, panic disorder, posttraumatic stress disorder and anxiety-relevant biological functions, discuss the limitations of classic conflict anxiety tests to measure naturally occurring sex differences in anxiety-like behaviors, describe sex-dependent manifestation of anxiety states after gestational, neonatal, or adolescent stressors, and present animal models of chronic anxiety states induced by acute or chronic stressors during adulthood.

Development × environment interactions control tph2 mRNA expression.

Adverse early life experience is thought to increase an individual's susceptibility to mental health disorders, including anxiety and affective disorders, later in life. Our previous studies have shown that post-weaning social isolation of female rats during a critical period of development sensitizes an anxiety-related serotonergic dorsal raphe nucleus (DR) system in adulthood. Therefore, we investigated how post-weaning social isolation, in combination with a challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142; a partial inverse agonist at the benzodiazepine allosteric site on the GABAA receptor), affects home cage behavior and serotonergic gene expression in the DR of female rats using in situ hybridization histochemistry.

Elevated tph2 mRNA expression in a rat model of chronic anxiety.

Background: Allelic variations in TPH2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-HT) biosynthesis, may be genetic predictors of panic disorder and panic responses to panicogenic challenges in healthy volunteers. To test the hypothesis that tph2 mRNA is altered in chronic anxiety states, we measured tph2 expression in an established rat model of panic disorder.

Methods: We implanted 16 adult, male rats with bilateral guide cannulae and then primed them with daily injections of the corticotropin-releasing factor (CRF) receptor agonist, urocortin 1 (UCN1, 6 fmoles/100 nl per side, n = 8) or vehicle (n = 8) into the basolateral amygdaloid complex (BL) for 5 consecutive days.

Swim stress activates serotonergic and nonserotonergic neurons in specific subdivisions of the rat dorsal raphe nucleus in a temperature-dependent manner.

Physical (exteroceptive) stimuli and emotional (interoceptive) stimuli are thought to influence stress-related physiologic and behavioral responses through different neural mechanisms. Previous studies have demonstrated that stress-induced activation of brainstem serotonergic systems is influenced by environmental factors such as temperature. In order to further investigate the effects of environmental influences on stress-induced activation of serotonergic systems, we exposed adult male Wistar rats to either home cage control conditions or a 15-min swim in water maintained at 19 °C, 25 °C, or 35 °C and conducted dual immunohistochemical staining for c-Fos, a marker of immediate-early nuclear activation, and tryptophan hydroxylase (TPH), a marker of serotonergic neurons.

Chronic non-invasive corticosterone administration abolishes the diurnal pattern of tph2 expression.

Both hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic systems are commonly dysregulated in stress-related psychiatric disorders. We describe here a non-invasive rat model for hypercortisolism, as observed in major depression, and its effects on physiology, behavior, and the expression of tph2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-hydroxytryptamine; 5-HT) synthesis. We delivered corticosterone (40 μg/ml, 100 μg/ml or 400 μg/ml) or vehicle to adrenal-intact adult, male rats via the drinking water for 3 weeks.

Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei.

Dysfunctions of the brain 5-HT system are often associated with affective disorders, such as depression. The raphe nuclei target the limbic system and most forebrain areas and constitute the main source of 5-HT in the brain. All 5-HT neurons express tryptophan hydroxylase-2 (TPH2), the brain specific, rate-limiting enzyme for 5-HT synthesis.