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Studies on the concurrent validity of clinically applicable testing protocols for conditioned pain modulation (CPM) and temporal summation of pain (TSP) in breast cancer survivors (BCS) with persistent pain are lacking.

Abstract The multifaceted nature of neuroinflammation is highlighted by its ability to both aggravate and promote neuronal health. While in mammals retinal ganglion cells (RGCs) are unable to regenerate following injury, acute inflammation can induce axonal regrowth. However, the nature of the cells, cellular states and signalling pathways that drive this inflammation-induced regeneration have remained elusive. Here, we investigated the functional significance of macrophages during RGC de- and regeneration, by characterizing the inflammatory cascade evoked by optic nerve crush (ONC) injury, with or without local inflammatory stimulation in the vitreous. By combining single-cell RNA sequencing and fate mapping approaches, we elucidated the response of retinal microglia and recruited monocyte-derived macrophages (MDMs) to RGC injury. Importantly, inflammatory stimulation recruited large numbers of MDMs to the retina, which exhibited long-term engraftment and promoted axonal regrowth. Ligand-receptor analysis highlighted a subset of recruited macrophages that exhibited expression of pro-regenerative secreted factors, which were able to promote axon regrowth via paracrine signalling. Our work reveals how inflammation may promote CNS regeneration by modulating innate immune responses, providing a rationale for macrophage-centred strategies for driving neuronal repair following injury and disease.

Abstract Background With over 500,000 annually reported cases worldwide, head and neck cancer (HNC) is the seventh most common type of cancer worldwide. Treatment of HNC with chemoradiotherapy frequently results in serious impairments in physical and psychosocial functioning. Besides, HNC patients typically start their cancer treatment already with poor physical and psychosocial health. It has been shown that a sufficient level of physical activity (PA) before, during, and after cancer treatment is associated with fewer negative treatment-related side effects and a better quality of life (QOL). In order to prevent worsening of functioning and limit the physical impact of the HNC treatment, a comprehensive supervised exercise program (CSEP) may be beneficial during early cancer treatment. However, up to now, the feasibility and effectiveness of such a program are not yet investigated thoroughly in HNC. Therefore, the primary objective of this study is to examine the effectiveness of a CSEP during HNC treatment, in addition to usual supportive care, compared to usual supportive care alone, on health-related QOL up to 1 year post-diagnosis. Secondary objectives entail gathering information on (1) the effectiveness of a CSEP on secondary outcomes such as physical and mental function, activities of daily life, and participation in society and (2) the feasibility, possible barriers, and facilitators for participation in a CSEP during HNC treatment. Methods To investigate the effectiveness of the CSEP, a parallel, open-label randomized controlled trial will be performed. To study the feasibility of the CSEP, a mixed-method study will be performed in a subgroup of participants. HNC patients are eligible if they receive radiotherapy at the Radiation-Oncology department of the University Hospital of Leuven. A 4-size permuted block randomization will be used. The control group receives the current standard of supportive care. The intervention group receives a CSEP, additional to the same usual supportive care. The CSEP consists of a 12-week intensive phase with 3 exercise sessions of 1 h per week, where supervision is gradually reduced after 6 weeks. During the maintenance phase (from week 13), patients exercise at home with monthly tele-consultations with a physiotherapist. The CSEP contains supervised aerobic and resistance training. In both groups, outcomes of interest are evaluated through self-reported questionnaires and clinical assessments, at baseline, 6 weeks, 12 weeks, 6 months, and 12 months post-diagnosis. The primary endpoint is health-related QOL, measured with the EORTC QLQ-C30 at 6 months post-diagnosis. Discussion The study will be conducted in accordance with the Declaration of Helsinki. This protocol has been approved by the ethical committee of the University Hospitals Leuven (s65549). Recruitment started in January 2022. Results will be disseminated via peer-reviewed scientific journals and presentations at congresses. Trial registration Trial Registration: ClinicalTrials.gov Identifier: NCT05256238 Date of registration: February 25, 2022

The highly-conserved Grainyhead-like (Grhl) transcription factors are critical regulators of embryogenesis that regulate cellular survival, proliferation, migration and epithelial integrity, especially during the formation of the craniofacial skeleton. Family member Grhl2 is expressed throughout epithelial tissues during development, and loss of Grhl2 function leads to significant defects in neurulation, abdominal wall closure, formation of the face and fusion of the maxilla/palate. Whereas numerous downstream target genes of Grhl2 have been identified, very little is known about how this crucial developmental transcription factor itself is regulated. Here, using in silico and in utero expression analyses and functional deletion in mice, we have identified a novel 2.4 ​kb enhancer element (mm1286) that drives reporter gene expression in a pattern that strongly recapitulates endogenous Grhl2 in the craniofacial primordia, modulates Grhl2 expression in these tissues, and augments Grhl2-mediated closure of the secondary palate. Deletion of this genomic element, in the context of inactivation of one allele of Grhl2 (through generation of double heterozygous Grhl2+/-;mm1286+/- mice), results in a significant predisposition to palatal clefting at birth. Moreover, we found that a highly conserved 325 bp region of mm1286 is both necessary and sufficient for mediating the craniofacial-specific enhancer activity of this region, and that an extremely well-conserved 12-bp sequence within this element (CTGTCAAACAGGT) substantially determines full enhancer function. Together, these data provide valuable new insights into the upstream genomic regulatory landscape responsible for transcriptional control of Grhl2 during palatal closure.

This article has been retracted; see accompanying Retraction Note, which can be accessed via a link at the top of the paper.

The highly-conserved Grainyhead-like (Grhl) transcription factors are critical regulators of embryogenesis that regulate cellular survival, proliferation, migration and epithelial integrity, especially during the formation of the craniofacial skeleton. Family member Grhl2 is expressed throughout epithelial tissues during development, and loss of Grhl2 function leads to significant defects in neurulation, abdominal wall closure, formation of the face and fusion of the maxilla/palate. Whereas numerous downstream target genes of Grhl2 have been identified, very little is known about how this crucial developmental transcription factor itself is regulated. Here, using in silico and in utero expression analyses and functional deletion in mice, we have identified a novel 2.4 ​kb enhancer element (mm1286) that drives reporter gene expression in a pattern that strongly recapitulates endogenous Grhl2 in the craniofacial primordia, modulates Grhl2 expression in these tissues, and augments Grhl2-mediated closure of the secondary palate. Deletion of this genomic element, in the context of inactivation of one allele of Grhl2 (through generation of double heterozygous Grhl2+/-;mm1286+/- mice), results in a significant predisposition to palatal clefting at birth. Moreover, we found that a highly conserved 325 bp region of mm1286 is both necessary and sufficient for mediating the craniofacial-specific enhancer activity of this region, and that an extremely well-conserved 12-bp sequence within this element (CTGTCAAACAGGT) substantially determines full enhancer function. Together, these data provide valuable new insights into the upstream genomic regulatory landscape responsible for transcriptional control of Grhl2 during palatal closure.

In the last decade, extracellular vesicles (EVs) have emerged as a promising field of research due to their ability to participate in cell-to-cell communication via the transfer of their very diverse and complex cargo. The latter reflects the nature and physiological state of the cell of origin and, as such, EVs may not only play a pivotal role in the cellular events that culminate into disease, but also hold great potential as drug delivery vehicles and biomarkers. Yet, their role in glaucoma, the leading cause of irreversible blindness worldwide, has not been fully studied. Here, we provide an overview of the different EV subtypes along with their biogenesis and content. We elaborate on how EVs released by different cell types can exert a specific function in the context of glaucoma. Finally, we discuss how these EVs provide opportunities to be used as biomarkers for diagnosis and monitoring of disease.

Musculoskeletal (MSK) pain is 1 of the most common problems managed by clinicians in MSK care. This article reviews current frameworks for the assessment and management of MSK pain within evidence-based physical therapy practice. Key considerations related to the biopsychosocial model of pain, evidence-based practice, assessment, treatment, physical activity/movement behavior, risk stratification, communication as well as patient education and self-management skills within physical therapy and physical and rehabilitation medicine are addressed. The future direction of MSK pain management is also discussed, including strategies to promote evidence-based practice, behavior change, social prescribing, and the use of technologies.

Abstract The gut microbiota represents a diverse and dynamic population of microorganisms that can influence the health of the host. Increasing evidence supports the role of the gut microbiota as a key player in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Unfortunately, the mechanisms behind the interplay between gut pathogens and AD are still elusive. It is known that bacteria‐derived outer membrane vesicles (OMVs) act as natural carriers of virulence factors that are central players in the pathogenesis of the bacteria. Helicobacter pylori (H. pylori) is a common gastric pathogen and H. pylori infection has been associated with an increased risk to develop AD. Here, we are the first to shed light on the role of OMVs derived from H. pylori on the brain in healthy conditions and on disease pathology in the case of AD. Our results reveal that H. pylori OMVs can cross the biological barriers, eventually reaching the brain. Once in the brain, these OMVs are taken up by astrocytes, which induce activation of glial cells and neuronal dysfunction, ultimately leading to exacerbated amyloid‐β pathology and cognitive decline. Mechanistically, we identified a critical role for the complement component 3 (C3)‐C3a receptor (C3aR) signalling in mediating the interaction between astrocytes, microglia and neurons upon the presence of gut H. pylori OMVs. Taken together, our study reveals that H. pylori has a detrimental effect on brain functionality and accelerates AD development via OMVs and C3‐C3aR signalling.

Context: The prevalence of persistent pain among breast cancer survivors (BCS) is high, and it is unclear what distinguishes those with persistent pain from those without. Research suggests that differences in somatosensory function evaluated by quantitative sensory testing (QST) may be responsible. Objectives: This study aimed to describe somatosensory profiles in terms of hyper‐ and hypoesthesia in BCS with and without persistent pain using reference data from healthy controls. Second, QST parameters of BCS with and without pain were compared with those of healthy controls (i.e., a negative control group) and patients with fibromyalgia (i.e., a positive control group). Methods: Participants (n = 128) were divided into four equal groups: healthy controls, BCS with persistent pain, BCS without persistent pain, and patients with fibromyalgia. Nine QST parameters were evaluated at the trunk and at a remote location. Somatosensory profiles were determined by Z‐score transformation of QST data using normative data from healthy controls. Results: At the trunk, compared to healthy controls, BCS with persistent pain exhibited sensory aberrations across five out of seven QST parameters: pressure pain threshold, mechanical detection, and thermal thresholds. Pain‐free BCS showed similar sensory aberrations across the four QST parameters compared to healthy controls: mechanical detection and thermal thresholds. Temporal summation and conditioned pain modulation were not significantly different between groups. Conclusion: BCS with persistent pain exert aberrations in peripheral processing of nociceptive signals, heightened facilitation of nociceptive signals, and higher psychosocial burden when compared to pain‐free BCS, healthy controls, and patients with fibromyalgia. Significance: This study investigates the somatosensory function of breast cancer survivors with and without persistent pain using quantitative sensory testing and two control group (i.e., patients with fibromyalgia and healthy controls). Our results indicate somatosensory aberrations within the peripheral, but not central pathways in breast cancer survivors with persistent pain. Our findings contribute to a better understanding of the somatosensory mechanisms underlying persistent pain, which may inform future interventions to prevent the development of persistent pain, and improve treatment modalities. [ABSTRACT FROM AUTHOR]

Abstract Background Overall survival rates after rectal cancer have increased. Therefore, functional outcomes rightly deserve more interest. The aims of this study were to assess progression in total, sports, occupational and household physical activity levels of rectal cancer survivors, from preoperatively to 12 months after surgery/stoma closure and to explore predictive factors. Methods Multi-center prospective study with 125 patients who underwent low anterior resection for rectal cancer. The Flemish Physical Activity Computerized Questionnaire was completed concerning all physical activity levels at baseline (past preoperative year) and at 1, 4, 6 and 12 months after surgery/stoma closure. At these timepoints, questionnaires (LARS−/ COREFO-questionnaire) regarding bowel symptoms were also filled out. Results were analyzed using linear mixed models for repeated measures. Results Total physical activity levels up to 12 months remained significantly lower than preoperative. Occupational and sports physical activity levels remained significantly lower until 6 and 4 months postoperative, respectively. Predictive factors for decreased physical activity levels at a specific timepoint were: younger age and no stoma (total physical activity, 1 month), low/mid rectal tumor, no stoma, non-employed status (total, 4 months), higher COREFO-scores (occupational, 4 months) and non-employed status (total, 12 months). At all timepoints, lower COREFO-scores were associated with higher total physical activity levels; male gender and lower educational levels with higher occupational levels; younger age, normal BMI, employed status and adjuvant therapy with higher sports levels; and female gender, lower educational level and unemployed status with higher household levels. Conclusions One year after rectal cancer treatment, total physical activity levels were still not recovered. Rectal cancer patients, especially those at risk for decreased physical activity levels and with major bowel complaints, should be identified and guided to increase their activities. Trial registration This trial has been registered at Netherlands Trial Register ( NTR6383 , 23/01/2017).

Abstract Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer’s and Parkinson’s disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish’s aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

Drosophila Insulin-Producing Cells (IPCs) are the main production site of the Drosophila Insulin-like peptides or dilps which have key roles in regulating growth, development, reproduction, lifespan and metabolism. To better understand the signalling pathways and transcriptional networks that are active in the IPCs we queried publicly available transcriptome data of over 180 highly inbred fly lines for dilp expression and used dilp expression as the input for a Genome-wide association study (GWAS). This resulted in the identification of variants in 125 genes that were associated with variation in dilp expression. The function of 57 of these genes in the IPCs was tested using an RNAi-based approach. We found that IPC-specific depletion of most genes resulted in differences in expression of one or more of the dilps. We then elaborated further on one of the candidate genes with the strongest effect on dilp expression, Homothorax, a transcription factor known for its role in eye development. We found that Homothorax and its binding partner Extradenticle are involved in regulating dilp2, -3 and -5 expression and that genetic depletion of both TFs shows phenotypes associated with reduced insulin signalling. Furthermore, we provide evidence that other transcription factors involved in eye development are also functional in the IPCs. In conclusion, we showed that this expression level-based GWAS approach identified genetic regulators implicated in IPC function and dilp expression.

(1) Background: Being able to objectively assess upper limb (UL) dysfunction in breast cancer survivors (BCS) is an emerging issue. This study aims to determine the accuracy of a pre-trained lab-based machine learning model (MLM) to distinguish functional from non-functional arm movements in a home situation in BCS. (2) Methods: Participants performed four daily life activities while wearing two wrist accelerometers and being video recorded. To define UL functioning, video data were annotated and accelerometer data were analyzed using a counts threshold method and an MLM. Prediction accuracy, recall, sensitivity, f1-score, ‘total minutes functional activity’ and ‘percentage functionally active’ were considered. (3) Results: Despite a good MLM accuracy (0.77–0.90), recall, and specificity, the f1-score was poor. An overestimation of the ‘total minutes functional activity’ and ‘percentage functionally active’ was found by the MLM. Between the video-annotated data and the functional activity determined by the MLM, the mean differences were 0.14% and 0.10% for the left and right side, respectively. For the video-annotated data versus the counts threshold method, the mean differences were 0.27% and 0.24%, respectively. (4) Conclusions: An MLM is a better alternative than the counts threshold method for distinguishing functional from non-functional arm movements. However, the abovementioned wrist accelerometer-based assessment methods overestimate UL functional activity.

Abstract Biological responses to stress are complex and highly conserved. Corticotropin-releasing factor (CRF) plays a central role in regulating these lifesaving physiological responses to stress. We show that, in mice, CRF rapidly changes Schaffer Collateral (SC) input into hippocampal CA1 pyramidal cells (PC) by modulating both functional and structural aspects of these synapses. Host exposure to acute stress, in vivo CRF injection, and ex vivo CRF application all result in fast de novo formation and remodeling of existing dendritic spines. Functionally, CRF leads to a rapid increase in synaptic strength of SC input into CA1 neurons, e.g., increase in spontaneous neurotransmitter release, paired-pulse facilitation, and repetitive excitability and improves synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD). In line with the changes in synaptic function, CRF increases the number of presynaptic vesicles, induces redistribution of vesicles towards the active zone, increases active zone size, and improves the alignment of the pre- and postsynaptic compartments. Therefore, CRF rapidly enhances synaptic communication in the hippocampus, potentially playing a crucial role in the enhanced memory consolidation in acute stress.