Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience.

Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Introducing a depression-like syndrome for translational neuropsychiatry: a plea for taxonomical validity and improved comparability between humans and mice.

Depressive disorders are the most burdensome psychiatric disorders worldwide. Although huge efforts have been made to advance treatment, outcomes remain unsatisfactory. Many factors contribute to this gridlock including suboptimal animal models. Especially limited study comparability and replicability due to imprecise terminology concerning depressive-like states are major problems. To overcome these issues, new approaches are needed. Here, we introduce a taxonomical concept for modelling depression in laboratory mice, which we call depression-like syndrome (DLS). It hinges on growing evidence suggesting that mice possess advanced socioemotional abilities and can display non-random symptom patterns indicative of an evolutionary conserved disorder-like phenotype. The DLS approach uses a combined heuristic method based on clinical depression criteria and the Research Domain Criteria to provide a biobehavioural reference syndrome for preclinical rodent models of depression. The DLS criteria are based on available, species-specific evidence and are as follows: (I) minimum duration of phenotype, (II) significant sociofunctional impairment, (III) core biological features, (IV) necessary depressive-like symptoms. To assess DLS presence and severity, we have designed an algorithm to ensure statistical and biological relevance of findings. The algorithm uses a minimum combined threshold for statistical significance and effect size (p value ≤ 0.05 plus moderate effect size) for each DLS criterion. Taken together, the DLS is a novel, biologically founded, and species-specific minimum threshold approach. Its long-term objective is to gradually develop into an inter-model validation standard and microframework to improve phenotyping methodology in translational research.

Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high-accuracy DNA methylation measurement via targeted bisulfite sequencing.

FKBP5 is an important stress-regulatory gene implicated in stress-related psychiatric diseases. Single nucleotide polymorphisms of the FKBP5 gene were shown to interact with early life stress to alter the glucocorticoid-related stress response and moderate disease risk. Demethylation of cytosine-phosphate-guanine-dinucleotides (CpGs) in regulatory glucocorticoid-responsive elements was suggested to be the mediating epigenetic mechanism for long-term stress effects, but studies on Fkbp5 DNA methylation (DNAm) in rodents are so far limited. We evaluated the applicability of high-accuracy DNA methylation measurement via targeted bisulfite sequencing (HAM-TBS), a next-generation sequencing-based technology, to allow a more in-depth characterisation of the DNA methylation of the murine Fkbp5 locus in three different tissues (blood, frontal cortex and hippocampus). In this study, we not only increased the number of evaluated sites in previously described regulatory regions (in introns 1 and 5), but also extended the evaluation to novel, possibly relevant regulatory regions of the gene (in intron 8, the transcriptional start site, the proximal enhancer and CTCF-binding sites within the 5'UTR). We here describe the assessment of HAM-TBS assays for a panel of 157 CpGs with possible functional relevance in the murine Fkbp5 gene. DNAm profiles were tissue-specific, with lesser differences between the two brain regions than between the brain and blood. Moreover, we identified DNAm changes in the Fkbp5 locus after early life stress exposure in the frontal cortex and blood. Our findings indicate that HAM-TBS is a valuable tool for broader exploration of the DNAm of the murine Fkbp5 locus and its involvement in the stress response.

Metabolic effects of early life stress and pre-pregnancy obesity are long lasting and sex specific in mice.

Early life stress (ELS) is associated with metabolic, cognitive, and psychiatric diseases and has a very high prevalence, highlighting the urgent need for a better understanding of the versatile physiological changes and identification of predictive biomarkers. In addition to programming the hypothalamic-pituitary-adrenal (HPA) axis, ELS may also affect the gut microbiota and metabolome, opening up a promising research direction for identifying early biomarkers of ELS-induced (mal)adaptation. Other factors affecting these parameters include maternal metabolic status and diet, with maternal obesity shown to predispose offspring to later metabolic disease. The aim of the present study was to investigate the long-term effects of ELS and maternal obesity on the metabolic and stress phenotype of rodent offspring. To this end, offspring of both sexes were subjected to an adverse early-life experience, and their metabolic and stress phenotypes were examined. In addition, we assessed whether a prenatal maternal and an adult high-fat diet (HFD) stressor further shape observed ELS-induced phenotypes. We show that ELS has long-term effects on male body weight (BW) across the lifespan, whereas females more successfully counteract ELS-induced weight loss, possibly by adapting their microbiota, thereby stabilizing a balanced metabolome. Furthermore, the metabolic effects of a maternal HFD on BW are exclusively triggered by a dietary challenge in adult offspring and are more pronounced in males than in females. Overall, our study suggests that the female microbiota protects against an ELS challenge, rendering them more resilient to additional maternal- and adult nutritional stressors than males.

SAFit2 ameliorates paclitaxel-induced neuropathic pain by reducing spinal gliosis and elevating pro-resolving lipid mediators.

BACKGROUND: Chemotherapy-induced neuropathic pain (CIPN) describes a pathological pain state that occurs dose-dependently as a side effect and can limit or even impede an effective cancer therapy. Unfortunately, current treatment possibilities for CIPN are remarkably confined and mostly inadequate as CIPN therapeutics themselves consist of low effectiveness and may induce severe side effects, pointing out CIPN as pathological entity with an emerging need for novel treatment targets. Here, we investigated whether the novel and highly specific FKBP51 inhibitor SAFit2 reduces paclitaxel-induced neuropathic pain. METHODS: In this study, we used a well-established multiple low-dose paclitaxel model to investigate analgesic and anti-inflammatory properties of SAFit2. For this purpose, the behavior of the mice was recorded over 14 days and the mouse tissue was then analyzed using biochemical methods. RESULTS: Here, we show that SAFit2 is capable to reduce paclitaxel-induced mechanical hypersensitivity in mice. In addition, we detected that SAFit2 shifts lipid levels in nervous tissue toward an anti-inflammatory and pro-resolving lipid profile that counteracts peripheral sensitization after paclitaxel treatment. Furthermore, SAFit2 reduced the activation of astrocytes and microglia in the spinal cord as well as the levels of pain-mediating chemokines. Its treatment also increased anti-inflammatory cytokines levels in neuronal tissues, ultimately leading to a resolution of neuroinflammation. CONCLUSIONS: In summary, SAFit2 shows antihyperalgesic properties as it ameliorates paclitaxel-induced neuropathic pain by reducing peripheral sensitization and resolving neuroinflammation. Therefore, we consider SAFit2 as a potential novel drug candidate for the treatment of paclitaxel-induced neuropathic pain.

Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity.

FKBP51 is an important inhibitor of the glucocorticoid receptor (GR) signaling. High FKBP51 levels are associated to stress-related disorders, which are linked to GR resistance. SUMO conjugation to FKBP51 is necessary for FKBP51's inhibitory action on GR. The GR/FKBP51 pathway is target of antidepressant action. Thus we investigated if these drugs could inhibit FKBP51 SUMOylation and therefore restore GR activity. Screening cells using Ni2+ affinity and in vitro SUMOylation assays revealed that tricyclic antidepressants- particularly clomipramine- inhibited FKBP51 SUMOylation. Our data show that clomipramine binds to FKBP51 inhibiting its interaction with PIAS4 and therefore hindering its SUMOylation. The inhibition of FKBP51 SUMOylation decreased its binding to Hsp90 and GR facilitating FKBP52 recruitment, and enhancing GR activity. Reduction of PIAS4 expression in rat primary astrocytes impaired FKBP51 interaction with GR, while clomipramine could no longer exert its inhibitory action. This mechanism was verified in vivo in mice treated with clomipramine. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential routes of antidepressant intervention.

From ligands to behavioral outcomes: understanding the role of mineralocorticoid receptors in brain function.

Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Persistent HPA axis overactivation or dysregulation can disrupt an individual's homeostasis, thereby contributing to an increased risk for mental illness. On the other hand, successful coping with stressful events involves adaptive and cognitive processes in the brain that render individuals more resilient to similar stressors in the future. Here we review the role of the MR in these processes, starting with an overview of the physiological structure, ligand binding, and expression of MR, and further summarizing its role in the brain, its relevance to psychiatric disorders, and related rodent studies. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders.

Plants with cosmetic uses.

The use of plants as a source of active principles for cosmetics has significantly increased in the last few years. Safety, compatibility with all types of skin, fewer side effects, and availability are among the advantages of herbal cosmetics above synthetic ingredients. The present review aims to explore the most important plants used in cosmetics. A literature search was carried out in several electronic databases with the following phrases: skincare and plants; cosmetics and plants; natural and cosmetics; and natural and skincare. Furthermore, more detailed filters such as clinical studies, meta-analyses, and systemic reviews were applied to positive results. Various plants and plant extracts currently used in skin care, scaring, whitening, and aging, as well as in sun protection, acne, eczema, and others, have been included in this review. The effectiveness of these plants is based mainly on preclinical research, and to a lesser extent on clinical studies. Some plant extracts or oils have been tested clinically, such as onions, aloe, and tea tree oil, more than other plant extracts. Despite many studies on natural products to improve dermal needs, proper clinical cosmeceutical trials are much fewer than expected. Therefore, more clinical trials are needed to evaluate appropriate efficacy. Furthermore, new formulation technologies might enhance the cosmeceutical benefits, but more work is warranted.

Impact of Pomegranate Juice on the Pharmacokinetics of CYP3A4- and CYP2C9-Mediated Drugs Metabolism: A Preclinical and Clinical Review.

The Punica granatum L. (pomegranate) fruit juice contains large amounts of polyphenols, mainly tannins such as ellagitannin, punicalagin, and punicalin, and flavonoids such as anthocyanins, flavan-3-ols, and flavonols. These constituents have high antioxidant, anti-inflammatory, anti-diabetic, anti-obesity, and anticancer activities. Because of these activities, many patients may consume pomegranate juice (PJ) with or without their doctor's knowledge. This may raise any significant medication errors or benefits because of food-drug interactions that modulate the drug's pharmacokinetics or pharmacodynamics. It has been shown that some drugs exhibited no interaction with pomegranate, such as theophylline. On the other hand, observational studies reported that PJ prolonged the pharmacodynamics of warfarin and sildenafil. Furthermore, since it has been shown that pomegranate constituents inhibit cytochrome P450 (CYP450) activities such as CYP3A4 and CYP2C9, PJ may affect intestinal and liver metabolism of CYP3A4 and CYP2C9-mediated drugs. This review summarizes the preclinical and clinical studies that investigated the impact of oral PJ administration on the pharmacokinetics of drugs that are metabolized by CYP3A4 and CYP2C9. Thus, it will serve as a future road map for researchers and policymakers in the fields of drug-herb, drug-food and drug-beverage interactions. Preclinical studies revealed that prolonged administration of PJ increased the absorption, and therefore the bioavailability, of buspirone, nitrendipine, metronidazole, saquinavir, and sildenafil via reducing the intestinal CYP3A4 and CYP2C9. On the other hand, clinical studies are limited to a single dose of PJ administration that needs to be protocoled with prolonged administration to observe a significant interaction.

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

BRAFV600E and BRAF-WT Specific Antitumor Immunity in Papillary Thyroid Cancer.

One feature of papillary thyroid cancer (PTC) is the frequently present somatic BRAFV600E mutation. PTCs are also characterized by a lymphocytic infiltration, which may correlate with an improved clinical outcome. The objective of the study was the characterization of BRAFV600E specific anti-immunity in PTC patients and correlation analyses with the clinical outcome. Fourteen HLA A2 positive PTC patients were included into the study of whom tumor tissue samples were also available. Of those, 8 PTC patients revealed a somatic BRAFV600E mutation. All PTC patients were also MHC class II typed. Tetramer analyses for detection of MHC class I and MHC class II-restricted, BRAFV600E epitope-specific T cells using unstimulated and peptide-stimulated T cells were performed; correlation analyses between MHC phenotypes, T cell immunity, and the clinical course were performed. In regard to unstimulated T cells, a significantly higher amount of BRAFV600E epitope specific T cells was detected compared to a control tetramer. Importantly, after overnight peptide stimulation a significantly higher number of BRAFV600E positive and BRAF WT epitope-specific T cells could be seen. In regard to the clinical course, however, no significant differences were seen, neither in the context of the initial tumor size, nor in the context of lymph node metastases or peripheral metastastic spread. In conclusion, we clearly demonstrated a BRAF-specific tumor immunity in PTC-patients which is, however, independent of a BRAFV600E status of the PTC patients.

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil.

In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.

Circadian gene × environment perturbations influence alcohol drinking in Cryptochrome-deficient mice.

Alcohol use disorder (AUD) is a widespread addiction disorder with severe consequences for health. AUD patients often suffer from sleep disturbances and irregular daily patterns. Conversely, disruptions of circadian rhythms are considered a risk factor for AUD and alcohol relapses. In this study, we investigated the extent to which circadian genetic and environmental disruptions and their interaction alter alcohol drinking behaviour in mice. As a model of genetic circadian disruption, we used Cryptochrome1/2-deficient (Cry1/2-/- ) mice with strongly suppressed circadian rhythms and found that they exhibit significantly reduced preference for alcohol but increased incentive motivation to obtain it. Similarly, we found that low circadian SCN amplitude correlates with reduced alcohol preference in WT mice. Moreover, we show that the low alcohol preference of Cry1/2-/- mice concurs with high corticosterone and low levels of the orexin precursor prepro-orexin and that WT and Cry1/2-/- mice respond differently to alcohol withdrawal. As a model of environmentally induced disruption of circadian rhythms, we exposed mice to a "shift work" light/dark regimen, which also leads to a reduction in their alcohol preference. Interestingly, this effect is even more pronounced when genetic and environmental circadian perturbations interact in Cry1/2-/- mice under "shift work" conditions. In conclusion, our study demonstrates that in mice, disturbances in circadian rhythms have pronounced effects on alcohol consumption as well as on physiological factors and other behaviours associated with AUD and that the interaction between circadian genetic and environmental disturbances further alters alcohol consumption behaviour.

Drug delivery for neuronopathic lysosomal storage diseases: evolving roles of the blood brain barrier and cerebrospinal fluid.

Whereas significant strides have been made in the treatment of lysosomal storage diseases (LSDs), the neuronopathy associated with these diseases remains impervious mainly because of the blood-brain barrier (BBB), which prevents delivery of large molecules to the brain. However, 100 years of research on the BBB since its conceptualization have clarified many of its functional and structural characteristics, spurring recent endeavors to deliver therapeutics across it to treat central nervous system (CNS) disorders, including neuronopathic LSDs. Along with the BBB, the cerebrospinal fluid (CSF) also functions to protect the microenvironment of the CNS, and it is therefore deeply involved in CNS disorders at large. Recent research aimed at developing therapeutics for neuronopathic LSDs has uncovered a number of critical roles played by the CSF that require further clarification. This review summarizes the most up-to-date understanding of the BBB and the CSF acquired during the development of therapeutics for neuronopathic LSDs, and highlights some of the associated challenges that require further research.

[The pathologist Hans Klein (1912-1984) : Autopsy of his role in the "Third Reich"]. / Der Pathologe Hans Klein (1912­1984) : Obduktion seiner Rolle im "Dritten Reich".

The role of pathologist Hans Klein during the National Socialist era and his career in post-war Germany have hardly received systematic attention. During World War II, Hans Klein worked in two medical institutions, where he collaborated with individuals who were significantly involved in Nazi crimes. Klein's participation initially extended mainly to his work as an employed pathologist at the Rudolf Virchow Hospital in Berlin. There he was introduced to autopsy practices in the context of the children's euthanasia programme and autopsies of victims of medical experiments. Later, a shift in his activities is noticeable at the Hohenlychen Sanatorium. Klein's activities there increasingly involved independent research or voluntary collaboration in the projects of other scientists that were closely connected to the SS and experiments on human beings in concentration camps. He never had to face justice. His role was not further investigated by the Allies - probably due to his non-existent Nazi party and SS membership.

[From Nazi to Hitler Analyst: The Autobiographical Reinterpretations of the Psychiatrist Johann Recktenwald (1882-1964)]. / Vom Nationalsozialisten zum Hitler-Erklärer: Die autobiografischen Umdeutungen des Psychiaters Johann Recktenwald (1882­1964).

AIM OF THE STUDY: The focus of this article is the psychiatrist Johann Recktenwald (1882-1964) who has so far received little attention: acquitted of the charge of "crimes against humanity", he went public in post-war Germany with a neuropsychiatric treatise on Hitler. But is this appearance as a Hitler-critical psychiatrist consistent with the available historical sources? What was Recktenwald's relationship with the Nazi regime, and how did he behave in the "Third Reich" towards the patients entrusted to his care? METHODS: The paper is largely based on documents from various archives, some of which have been evaluated for the first time, and on court records. The latter are supplemented and compared with the writings of Recktenwald and the available secondary literature. RESULTS: During the "Third Reich", Recktenwald served the Nazi regime in many ways, was jointly responsible for numerous patient murders and thus moved into the role of a Nazi perpetrator. After his acquittal in post-war Germany, he endeavored to construct a personal distance to National Socialism by critically examining Hitler's psychopathology, which at the same time served his own exculpation. CONCLUSION: Recktenwald is a particularly impressive example of the efforts of Nazi perpetrators to retrospectively rewrite their own role in the "Third Reich" - and at the same time a reflection of a post-war society that was willing to accept such biographical reinterpretations in order to avoid coming to terms with the Nazi past.

Loss of the psychiatric risk factor SLC6A15 is associated with increased metabolic functions in primary hippocampal neurons.

Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome-wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue from Slc6a15-KO and wild-type mice, together with several in-vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy.

Radioiodine therapy reduces the frequency of circulating tumour cells in patients with differentiated thyroid cancer.

OBJECTIVE: The aim of the study was the quantification of circulating tumour cells (CTCs) in differentiated thyroid cancer (DTC) patients before and 6 weeks after radioiodine therapy (RIT). CONTEXT: Circulating tumour cells (CTCs) were described more recently in cancer patients, mostly correlating with poor outcome and advanced metastases. DESIGN: Peripheral blood for identification and quantification of CTC before RIT or/and 6 weeks after RIT was provided by 55 DTC patients that received RIT for remnant tissue ablation. PATIENTS: 13 follicular thyroid cancer (FTC) patients, 31 papillary thyroid cancer (PTC) patients and 11 patients having the follicular variant PTC (FV-PTC) were included. MEASUREMENTS: Peripheral blood mononuclear cells (PBMCs) were isolated and EpCAM-positive CTCs were counted by immune fluorescent staining. RESULTS: A CTC positivity of 31.8% before RIT could be observed. Six weeks after RIT, the CTC positivity was reduced to 13.6%. Paired data at both time points of blood sampling could be gathered for n = 33 DTC patients. These patients had significantly higher CTC numbers before RIT than 6 weeks afterwards (0.27 ± 0.47 vs 0.05 ± 0.15, P = .0215). Additionally, significantly reduced CTC numbers were also demonstrated in pre-RIT CTC-positive patients (0.88 ± 0.43 vs 0.05 ± 0.16, P = .0039). CONCLUSION: Our results indicate a reducing effect on the number of CTCs by RIT. Therefore, CTC enumeration should be considered as efficient tool for treatment monitoring during RIT.

Lack of FKBP51 Shapes Brain Structure and Connectivity in Male Mice.

BACKGROUND: Stress exposure as well as psychiatric disorders are often associated with abnormalities in brain structure or connectivity. The co-chaperone FK506-binding protein 51 (FKBP51) is a regulator of the stress system and is associated with a risk to develop stress-related mental illnesses. PURPOSE: To assess the effect of a general FKBP51 knockout on brain structure and connectivity in male mice. STUDY TYPE: Animal study. ANIMAL MODEL: Two cohorts of FKBP51 knockout (51KO) and wildtype (WT) mice. The first cohort was comprised of n = 18 WT and n = 17 51KOs; second cohort n = 10 WT and n = 9 51KOs. FIELD STRENGTH/SEQUENCE: 9.4T/3D gradient echo (VBM), DTI-EPI (DTI). ASSESSMENT: Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). For VBM, all procedures were executed in SPM12. DTI: FMRIB Software Library (FSL) Tract Based Statistics (TBSS) were integrated within DTI-TK, allowing the creation of a mean FA skeleton. A voxelwise statistical analysis was applied between WT and 51KO mice. STATISTICAL TEST: Volumetric differences were collected at a threshold of P < 0.005, and only clusters surviving a familywise error correction on the cluster level (pFWE, cluster <0.05) were further considered. VBM data were analyzed using a two-sample t-test. The Threshold Free Cluster Enhancement (TFCE) method was used to derive uncorrected-P statistical results at a P-level of 0.01. RESULTS: The structural analysis revealed two clusters of significantly larger volumes in the hypothalamus, periaqueductal gray, and dorsal raphe region of WT animals. DTI measurements, however, demonstrated statistically higher fractional anisotropy (FA) values for 51KO animals in locations including the anterior commissure, fornix, and posterior commissure/superior colliculus commissure region. DATA CONCLUSION: This study used in vivo structural MRI and DTI to demonstrate that a lack of FKBP51 leads to alterations in brain architecture and connectivity in male mice. These findings are of particular translational relevance for our understanding of the neuroanatomy underlying the interaction of FKBP5 genetic status, stress susceptibility, and psychiatric disorders. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.