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Hematology/oncology Clinics of North... May 2024This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the... (Review)
Review
This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the risk of malignancy. Oral potentially malignant disorders, notably leukoplakia, are discussed as precursors influenced by genetic and immunologic facets. Molecular insights delve into genetic mutations, allelic imbalances, and immune modulation as key players in precancerous progression, suggesting potential therapeutic targets. The article navigates the controversial terrain of management strategies of leukoplakia, encompassing surgical resection, chemoprevention, and immune modulation, while emphasizing the ongoing challenges in developing effective, evidence-based preventive approaches.
PubMed: 38705773
DOI: 10.1016/j.hoc.2024.04.001 -
Developmental Cell Jan 2024Fetal bone development occurs through the conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of...
Fetal bone development occurs through the conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we show that the mechanoresponsive transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular morphogenesis to control cartilage remodeling, and mediate mechanoregulation of embryonic murine osteogenesis. Mechanistically, YAP and TAZ regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors, which regulate transcriptional programs that direct blood vessel invasion through collagen-integrin interactions and Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescues angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish functions of the vessel-associated osteoblast precursors in bone development.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Angiogenesis; Bone Development; Morphogenesis; Osteoblasts; Trans-Activators; Transcription Factors; YAP-Signaling Proteins
PubMed: 38141609
DOI: 10.1016/j.devcel.2023.11.029 -
Glia Sep 2023Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, a process that may be tuned by neuronal activity, possibly via synaptic connections to OPCs. However, a...
Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, a process that may be tuned by neuronal activity, possibly via synaptic connections to OPCs. However, a developmental role of synaptic signaling to OPCs has so far not been shown unequivocally. To address this question, we comparatively analyzed functional and molecular characteristics of highly proliferative and migratory OPCs in the embryonic brain. Embryonic OPCs in mice (E18.5) shared the expression of voltage-gated ion channels and their dendritic morphology with postnatal OPCs, but almost completely lacked functional synaptic currents. Transcriptomic profiling of PDGFRα OPCs revealed a limited abundance of genes coding for postsynaptic signaling and synaptogenic cell adhesion molecules in the embryonic versus the postnatal period. RNA sequencing of single OPCs showed that embryonic synapse-lacking OPCs are found in clusters distinct from postnatal OPCs and with similarities to early progenitors. Furthermore, single-cell transcriptomics demonstrated that synaptic genes are transiently expressed only by postnatal OPCs until they start to differentiate. Taken together, our results indicate that embryonic OPCs represent a unique developmental stage biologically resembling postnatal OPCs but without synaptic input and a transcriptional signature in the continuum between OPCs and neural precursors.
Topics: Mice; Animals; Oligodendrocyte Precursor Cells; Mice, Transgenic; Oligodendroglia; Neurons; Neurogenesis; Cell Differentiation
PubMed: 37226895
DOI: 10.1002/glia.24388 -
Molecular Cell Aug 2023Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion...
Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like intermediates and dHJs in mouse. In contrast to yeast, MLH3 is structurally required to differentiate CO precursors into dHJs. We verify conservation of aspects of meiotic recombination and show unique features in mouse, providing mechanistic insight into CO formation.
Topics: Animals; Mice; Saccharomyces cerevisiae; Meiosis; Chromosome Segregation; DNA, Cruciform; Mammals
PubMed: 37595556
DOI: 10.1016/j.molcel.2023.07.022 -
Bioresource Technology Aug 2023β-Farnesene is a sesquiterpene commonly found in essential oils of plants, with applications spanning from agricultural pest control and biofuels to industrial...
β-Farnesene is a sesquiterpene commonly found in essential oils of plants, with applications spanning from agricultural pest control and biofuels to industrial chemicals. The use of renewable substrates in microbial cell factories offers a sustainable approach to β-farnesene biosynthesis. In this study, malic enzyme from Mucor circinelloides was examined for NADPH regeneration, concomitant with the augmentation of cytosolic acetyl-CoA supply by expressing ATP-citrate lyase from Mus musculus and manipulating the citrate pathway via AMP deaminase and isocitrate dehydrogenase. Carbon flux was modulated through the elimination of native 6-phosphofructokinase, while the incorporation of an exogenous non-oxidative glycolysis pathway served to bridge the pentose phosphate pathway with the mevalonate pathway. The resulting orthogonal precursor supply pathway facilitated β-farnesene production, reaching 810 mg/L in shake-flask fermentation. Employing optimal fermentation conditions and feeding strategy, a titer of 28.9 g/L of β-farnesene was attained in a 2 L bioreactor.
Topics: Animals; Mice; Yarrowia; Fermentation; Bioreactors; Sesquiterpenes; Metabolic Engineering
PubMed: 37196740
DOI: 10.1016/j.biortech.2023.129171 -
Molecules (Basel, Switzerland) Mar 2024During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in... (Review)
Review
During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in clinical practice. In addition to exploring new antibiotics, this makes it one of the research priorities of to effectively increase the yield of antibiotics in production strains by various means. Most antibiotic-producing strains have a variety of functional regulatory factors that regulate their growth, development, and secondary metabolite biosynthesis processes. Through the study of precursor substances in antibiotic biosynthesis, researchers have revealed the precursor biosynthesis process and the mechanism by which precursor synthesis regulators affect the biosynthesis of secondary metabolites, which can be used to obtain engineered strains with high antibiotic production. This paper summarizes the supply of antibiotic biosynthesis precursors and the progress of research on the role of regulators in the process of precursors in biosynthesis. This lays the foundation for the establishment of effective breeding methods to improve antibiotic yields through the manipulation of precursor synthesis genes and related regulators.
Topics: Anti-Bacterial Agents; Actinobacteria; Actinomyces; Secondary Metabolism
PubMed: 38474644
DOI: 10.3390/molecules29051132 -
Neuroimmunomodulation 2024T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is... (Review)
Review
BACKGROUND
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is generally thought to originate in the thymus since lymphoblasts express phenotypic markers comparable to those described in thymocytes in distinct stages of development. Although around 50% of T-ALL patients present a thymic mass, T-ALL is characterized by peripheral blood and bone marrow involvement, and central nervous system (CNS) infiltration is one of the most severe complications of the disease.
SUMMARY
The CNS invasion is related to the expression of specific adhesion molecules and receptors commonly expressed in developing T cells, such as L-selectin, CD44, integrins, and chemokine receptors. Furthermore, T-ALL blasts also express neurotransmitters, neuropeptides, and cognate receptors that are usually present in the CNS and can affect both the brain and thymus, participating in the crosstalk between the organs.
KEY MESSAGES
This review discusses how the thymus-brain connections, mediated by innervation and common molecules and receptors, can impact the development and migration of T-ALL blasts, including CNS infiltration.
Topics: Humans; Thymus Gland; Brain; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Animals
PubMed: 38272012
DOI: 10.1159/000536419 -
Virulence Dec 2024Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers...
Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers susceptibility and progression, recently attracting considerable attention. This study aimed to determine the infection status and relationship between high-risk HPV (HR-HPV) and lower genital tract infectious pathogens in cervical cancer and its precursors. From a retrospective and a prospective cohort analysis, () dominated the pathogens isolated from cervical discharges, and an isolation rate uptrend has been shown recently. HPV16 and 's coinfection rate gradually increased with the severity of cervical intraepithelial neoplasia. The adhesion and invasion abilities of the isolated to HPV16-positive SiHa cells were evaluated . The TCGA database and cervical tissues samples analysis showed that IL-10 was upregulated in cervical cancer. IL-10 expression levels increased in tissue samples with the severity of cervical cancer and its precursors with HPV16 and coinfection. Although no significant changes in IL-10 production were observed in the co-culture supernatant, we hypothesized that Treg immune cells in the tumour microenvironment might be responsible for the local IL-10 upregulation, according to our data showing Foxp3 upregulation and an upward trend with the cervical intraepithelial neoplasia grading to cancer and tumours with and HPV16 coinfection. Our data provide insights into the possible role of in cervical cancer progression and suggest that the application of HPV and screening programs may be an effective strategy to relieve the burden of cervical cancer and its precursor lesions.
Topics: Female; Humans; Uterine Cervical Neoplasms; Interleukin-10; Human papillomavirus 16; Escherichia coli; Papillomavirus Infections; Retrospective Studies; Coinfection; Prospective Studies; Uterine Cervical Dysplasia; Tumor Microenvironment
PubMed: 38380669
DOI: 10.1080/21505594.2024.2319962 -
Genomics, Proteomics & Bioinformatics May 2024Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies,... (Review)
Review
Ribonuclease P (RNase P) was first described in the 1970's as an endoribonuclease acting in the maturation of precursor transfer RNAs (tRNAs). More recent studies, however, have uncovered non-canonical roles for RNase P and its components. Here, we review the recent progress of its involvement in chromatin assembly, DNA damage response, and maintenance of genome stability with implications in tumorigenesis. The possibility of RNase P as a therapeutic target in cancer is also discussed.
Topics: Ribonuclease P; Humans; RNA, Transfer; Neoplasms; RNA Precursors; Genomic Instability; Animals; DNA Damage; RNA Processing, Post-Transcriptional; Chromatin Assembly and Disassembly
PubMed: 38862431
DOI: 10.1093/gpbjnl/qzae016 -
The American Journal of Surgical... Dec 2023Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We...
Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing ( P <0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P <0.001), p53 overexpression (26/42; P <0.001), and hotspot mutations in TP53 (32/42; P <0.001), CDKN2A (26/42; P <0.001) or both (21/42; P =0.003) in the adjacent SCC. Cytoplasmic p16 ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P <0.001) occurred adjacent to verrucous or papillary SCC (17/21; P <0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P <0.004). Undifferentiated p16 ink4a -negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS .
Topics: Male; Female; Humans; Papillomavirus Infections; Tumor Suppressor Protein p53; Human Papillomavirus Viruses; Skin Neoplasms; Carcinoma in Situ; Carcinoma, Squamous Cell; Penile Neoplasms; Penis; Papillomaviridae; Class I Phosphatidylinositol 3-Kinases; Vulvar Neoplasms
PubMed: 37768009
DOI: 10.1097/PAS.0000000000002130