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Cell Research Mar 2020Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining...
Recent studies have shown that meningeal lymphatic vessels (MLVs), which are located both dorsally and basally beneath the skull, provide a route for draining macromolecules and trafficking immune cells from the central nervous system (CNS) into cervical lymph nodes (CLNs), and thus represent a potential therapeutic target for treating neurodegenerative and neuroinflammatory diseases. However, the roles of MLVs in brain tumor drainage and immunity remain unexplored. Here we show that dorsal MLVs undergo extensive remodeling in mice with intracranial gliomas or metastatic melanomas. RNA-seq analysis of MLV endothelial cells revealed changes in the gene sets involved in lymphatic remodeling, fluid drainage, as well as inflammatory and immunological responses. Disruption of dorsal MLVs alone impaired intratumor fluid drainage and the dissemination of brain tumor cells to deep CLNs (dCLNs). Notably, the dendritic cell (DC) trafficking from intracranial tumor tissues to dCLNs decreased in mice with defective dorsal MLVs, and increased in mice with enhanced dorsal meningeal lymphangiogenesis. Strikingly, disruption of dorsal MLVs alone, without affecting basal MLVs or nasal LVs, significantly reduced the efficacy of combined anti-PD-1/CTLA-4 checkpoint therapy in striatal tumor models. Furthermore, mice bearing tumors overexpressing VEGF-C displayed a better response to anti-PD-1/CTLA-4 combination therapy, and this was abolished by CCL21/CCR7 blockade, suggesting that VEGF-C potentiates checkpoint therapy via the CCL21/CCR7 pathway. Together, the results of our study not only demonstrate the functional aspects of MLVs as classic lymphatic vasculature, but also highlight that they are essential in generating an efficient immune response against brain tumors.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glioma; HEK293 Cells; Humans; Lymphatic Vessels; Male; Melanoma; Melanoma, Experimental; Meninges; Mice; Mice, Inbred C57BL; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 32094452
DOI: 10.1038/s41422-020-0287-8 -
Cell Jan 2023The cortex influences movement by widespread top-down projections to many nervous system regions. Skilled forelimb movements require brainstem circuitry in the medulla;...
The cortex influences movement by widespread top-down projections to many nervous system regions. Skilled forelimb movements require brainstem circuitry in the medulla; however, the logic of cortical interactions with these neurons remains unexplored. Here, we reveal a fine-grained anatomical and functional map between anterior cortex (AC) and medulla in mice. Distinct cortical regions generate three-dimensional synaptic columns tiling the lateral medulla, topographically matching the dorso-ventral positions of postsynaptic neurons tuned to distinct forelimb action phases. Although medial AC (MAC) terminates ventrally and connects to forelimb-reaching-tuned neurons and its silencing impairs reaching, lateral AC (LAC) influences dorsally positioned neurons tuned to food handling, and its silencing impairs handling. Cortico-medullary neurons also extend collaterals to other subcortical structures through a segregated channel interaction logic. Our findings reveal a precise alignment between cortical location, its function, and specific forelimb-action-tuned medulla neurons, thereby clarifying interaction principles between these two key structures and beyond.
Topics: Mice; Animals; Movement; Neurons; Forelimb; Brain Stem
PubMed: 36608651
DOI: 10.1016/j.cell.2022.12.009 -
Journal of Chemical Neuroanatomy Dec 2020A recent cluster of reports have considerably deepened our understanding of the transcriptional diversity of serotonin neurons of the dorsal raphe nucleus (DR). In this... (Review)
Review
A recent cluster of reports have considerably deepened our understanding of the transcriptional diversity of serotonin neurons of the dorsal raphe nucleus (DR). In this commentary a subset of implications from these studies is highlighted such as: serotonin neurons in the lateral wings have a newly discovered close relationship with those in rostral and dorsal locations and that cre-lines may be just as likely to cut across several transcriptional subtypes as to define a single subtype. To evolve understanding of DR organization, it may be prudent to correlate transcriptional snapshots in time with other known features of DR neurons. Here we bring together new and old information on serotonin neuron diversity with the goal of developing increasingly useful schemes of DR organization.
Topics: Animals; Dorsal Raphe Nucleus; Humans; Neurons; Serotonin; Vesicular Glutamate Transport Proteins
PubMed: 33031916
DOI: 10.1016/j.jchemneu.2020.101868 -
European Review For Medical and... Mar 2023The aim of this paper is to investigate the efficacy of filler applications which were evaluated in terms of nasal deformity and quality of life of the patients, and to...
OBJECTIVE
The aim of this paper is to investigate the efficacy of filler applications which were evaluated in terms of nasal deformity and quality of life of the patients, and to review the fillers around the nose.
PATIENTS AND METHODS
Forty patients who underwent filler application were included into the study and were divided into Group 1 (Deep Radix), Group 2 (Minor irregularities due to rhinoplasty), Group 3 (Shallow dorsum) and Group 4 (Dorsal irregularity). There were 10 patients in each of the groups. In all groups, nasal deformity score was evaluated with a 1 to 5 scale as following: 1- No deformity, 2- Hardly visible deformity, 3- Visible deformity, 4- Moderate deformity, 5- Apparent deformity. Quality of life was evaluated by a 1 to 10 scale, 1 showing very low and 10 showing very high.
RESULTS
Our results showed that there were statistically significant improvements (decreased) in nasal deformity evaluation scores after the procedure compared to the before the procedure scores in Group 1 (Deep Radix), Group 3 (Shallow dorsum) and Group 4 (Dorsal irregularity) (p<0.05) However in Group 2 (Minor irregularities due to rhinoplasty), there were no significant differences between the nasal deformity evaluation scores after and before the procedure (p>0.05). For nasal deformity evaluation after the procedure, Group 1 (Deep Radix), Group 3 (Shallow dorsum) and Group 4 (Dorsal irregularity) scores were significantly lower (better) than Group 2 (Minor irregularities due to rhinoplasty) scores (padjusted <0.0125). In all four groups (Deep Radix, Minor irregularities due to rhinoplasty, Shallow dorsum, Dorsal irregularity), quality of life scores were significantly improved (increased) after the procedure compared to before the procedure (p<0.05). For Quality of life (VAS) before the procedure, Group 3 (Shallow dorsum) scores were significantly higher (improved, increased) than Group 1 (Deep Radix) and Group 4 (Dorsal irregularity) (padjusted <0.0125).
CONCLUSIONS
Filler applications improved (decreased) nasal deformity evaluation scores and improved (increased) quality of life scores. Fillers can be applied for deep radix, minor irregularities due to rhinoplasty, shallow dorsum and dorsal irregularity. It is essential to choose carefully appropriate materials and procedures for patients to obtain optimum results.
Topics: Humans; Quality of Life; Nose; Rhinoplasty
PubMed: 36971217
DOI: 10.26355/eurrev_202303_31697 -
Purinergic Signalling Mar 2021Purinergic signalling plays important roles in somatosensory and nociceptive transmission in the dorsal horn of the spinal cord under physiological and... (Review)
Review
Purinergic signalling plays important roles in somatosensory and nociceptive transmission in the dorsal horn of the spinal cord under physiological and pathophysiological conditions. Physiologically, ATP mediates excitatory postsynaptic responses in nociceptive transmission in the superficial dorsal horn, and in transmission of innocuous primary afferent inputs in the deep dorsal horn. Additionally, extracellular conversion of ATP to adenosine mediates inhibitory postsynaptic responses from Pacinian corpuscle afferents, and is implicated in analgesia caused by transcutaneous electrical nerve stimulation in humans. In terms of pathological pain, P2X4 receptors de novo expressed on dorsal horn microglia are implicated in pain hypersensitivity following peripheral nerve injury. There is evidence that involvement of such P2X4 receptors is sexually dimorphic, occurring in males but not in females. Thus, the roles of purinergic signalling in physiological and pathological pain processing are complex and remain an ever-expanding field of research.
Topics: Adenosine Triphosphate; Animals; Disease Models, Animal; Humans; Microglia; Neuralgia; Posterior Horn Cells; Receptors, Purinergic; Spinal Cord Dorsal Horn
PubMed: 33169292
DOI: 10.1007/s11302-020-09748-5