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International Journal of Molecular... Aug 2020Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and... (Review)
Review
Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and genetic factors. However, despite the progress in the field, BCC biology and mechanisms of resistance against systemic treatments have been poorly investigated. The aim of the present review is to provide a revision of BCC histological and molecular features, including microRNA (miRNA) dysregulation, with a specific focus on the molecular basis of BCC systemic therapies. Papers from the last ten years regarding BCC genetic and phenotypic alterations, as well as the mechanism of resistance against hedgehog pathway inhibitors vismodegib and sonidegib were included. The involvement of miRNAs in BCC resistance to systemic therapies is emerging as a new field of knowledge.
Topics: Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; MicroRNAs; Pyridines
PubMed: 32759706
DOI: 10.3390/ijms21155572 -
Acta Dermato-venereologica Jun 2020Basal cell carcinomas are the most frequent skin cancers in the fair-skinned adult population over 50 years of age. Their incidence is increasing throughout the world.... (Review)
Review
Basal cell carcinomas are the most frequent skin cancers in the fair-skinned adult population over 50 years of age. Their incidence is increasing throughout the world. Ultraviolet (UV) exposure is the major carcinogenic factor. Some genodermatosis can predispose to formation of basal cell carcinomas at an earlier age. Basal cell carcinomas are heterogeneous, from superficial or nodular lesions of good prognosis to very extensive difficult-to-treat lesions that must be discussed in multidisciplinary committees. Recent guidelines have updated the management of basal cell carcinoma. The prognosis is linked to the risk of recurrence of basal cell carcinoma or its local destructive capacity. Characteristic molecular events in these tumours are: (i) activation of the hedgehog pathway, which has allowed the development of hedgehog inhibitors for difficult-to-treat lesions that are not accessible to surgery or radiotherapy; (ii) high mutational burden, which suggests that hedgehog inhibitor refractory tumours could be offered immunotherapy; some trials are ongoing. The standard treatment for most basal cell carcinomas is surgery, as it allows excision margin control and shows a low risk of recurrence. Superficial lesions can be treated by non-surgical methods with significant efficacy.
Topics: Biomarkers, Tumor; Carcinoma, Basal Cell; Dermatologic Surgical Procedures; Genetic Predisposition to Disease; Humans; Immunotherapy; Molecular Targeted Therapy; Mutation; Phenotype; Skin Neoplasms; Treatment Outcome
PubMed: 32346750
DOI: 10.2340/00015555-3495 -
The FEBS Journal Apr 2022The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important... (Review)
Review
The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.
Topics: AMP-Activated Protein Kinases; Animals; Astrocytes; Brain; Energy Metabolism; Glucose; Glycogen; Mice
PubMed: 34355526
DOI: 10.1111/febs.16151 -
Neurological Sciences : Official... Nov 2019Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms... (Review)
Review
Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.
Topics: Autoimmune Diseases of the Nervous System; Basal Ganglia Diseases; Calcinosis; Cockayne Syndrome; Humans; Hypoparathyroidism; Lupus Vasculitis, Central Nervous System; Mitochondrial Diseases; Nervous System Malformations; Neurodegenerative Diseases; Neurotoxicity Syndromes; Pseudohypoparathyroidism; Xenotropic and Polytropic Retrovirus Receptor
PubMed: 31267306
DOI: 10.1007/s10072-019-03998-x -
American Journal of Respiratory Cell... Mar 2023Loss of epithelial integrity, bronchiolarization, and fibroblast activation are key characteristics of idiopathic pulmonary fibrosis (IPF). Prolonged accumulation of...
Loss of epithelial integrity, bronchiolarization, and fibroblast activation are key characteristics of idiopathic pulmonary fibrosis (IPF). Prolonged accumulation of basal-like cells in IPF may impact the fibrotic niche to promote fibrogenesis. To investigate their role in IPF, basal cells were isolated from IPF explant and healthy donor lung tissues. Single-cell RNA sequencing was used to assess differentially expressed genes in basal cells. Basal cell and niche interaction was demonstrated with the sLP-mCherry niche labeling system. Luminex assays were used to assess cytokines secreted by basal cells. The role of basal cells in fibroblast activation was studied. Three-dimensional organoid culture assays were used to interrogate basal cell effects on AEC2 (type 2 alveolar epithelial cell) renewal capacity. Perturbation was used to investigate WNT7A function and in a repetitive bleomycin model . We found that WNT7A is highly and specifically expressed in basal-like cells. Proteins secreted by basal cells can be captured by neighboring fibroblasts and AEC2s. Basal cells or basal cell-conditioned media activate fibroblasts through WNT7A. Basal cell-derived WNT7A inhibits AEC2 progenitor cell renewal in three-dimensional organoid cultures. Neutralizing antibodies against WNT7A or a small molecule inhibitor of Frizzled signaling abolished basal cell-induced fibroblast activation and attenuated lung fibrosis in mice. In summary, basal cells and basal cell-derived WNT7A are key components of the fibrotic niche, providing a unique non-stem cell function of basal cells in IPF progression and a novel targeting strategy for IPF.
Topics: Animals; Mice; Bleomycin; Fibroblasts; Fibrosis; Idiopathic Pulmonary Fibrosis; Lung; Signal Transduction
PubMed: 36318668
DOI: 10.1165/rcmb.2022-0074OC -
Journal of the American Academy of... Sep 2021Multiple studies have reported on dermoscopic structures in basal cell carcinoma (BCC) and its subtypes, with varying results.
BACKGROUND
Multiple studies have reported on dermoscopic structures in basal cell carcinoma (BCC) and its subtypes, with varying results.
OBJECTIVE
To systematically review the prevalence of dermoscopic structures in BCC and its subtypes.
METHODS
Databases and reference lists were searched for relevant trials according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were assessed for the relative proportion of BCC dermoscopic features. Random-effects models were used to estimate summary effect sizes.
RESULTS
Included were 31 studies consisting of 5950 BCCs. The most common dermoscopic features seen in BCC were arborizing vessels (59%), shiny white structures (49%), and large blue-grey ovoid nests (34%). Arborizing vessels, ulceration, and blue-grey ovoid nests and globules were most common in nodular BCC; short-fine telangiectasia, multiple small erosions, and leaf-like, spoke wheel and concentric structures in superficial BCC; porcelain white areas and arborizing vessels in morpheaform BCC; and arborizing vessels and ulceration in infiltrative BCC.
LIMITATIONS
Studies had significant heterogeneity. Studies reporting BCC histopathologic subtypes did not provide clinical data on pigmentation of lesions.
CONCLUSION
In addition to arborizing vessels, shiny white structures are a common feature of BCC. A constellation of dermoscopic features may aid in differentiating between BCC histopathologic subtypes.
Topics: Carcinoma, Basal Cell; Dermoscopy; Humans; Pigmentation; Pigmentation Disorders; Skin Neoplasms
PubMed: 31706938
DOI: 10.1016/j.jaad.2019.11.008 -
Cellular & Molecular Immunology Jun 2023Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and... (Review)
Review
Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.
Topics: Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Osteoarthritis, Knee; Pain; Treatment Outcome; Randomized Controlled Trials as Topic; Non-Randomized Controlled Trials as Topic
PubMed: 37095295
DOI: 10.1038/s41423-023-01020-1 -
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 -
ELife Aug 2022Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both...
Infections at the maternal-fetal interface can directly harm the fetus and induce complications that adversely impact pregnancy outcomes. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed matched trophoblast (TO) and decidua organoids (DO) from human placentas to define the relative contributions of these cells to antiviral defenses at the maternal-fetal interface. We demonstrate that TO and DO basally secrete distinct immunomodulatory factors, including the constitutive release of the antiviral type III interferon IFN-λ2 from TOs, and differentially respond to viral infections through the induction of organoid-specific factors. Finally, we define the differential susceptibility and innate immune signaling of TO and DO to human cytomegalovirus (HCMV) and develop a co-culture model of TO and DO which showed that trophoblast-derived factors protect decidual cells from HCMV infection. Our findings establish matched TO and DO as ex vivo models to study vertically transmitted infections and highlight differences in innate immune signaling by fetal-derived trophoblasts and the maternal decidua.
Topics: Antiviral Agents; Decidua; Female; Humans; Immunity, Innate; Organoids; Placenta; Pregnancy; Trophoblasts
PubMed: 35975985
DOI: 10.7554/eLife.79794