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ACS Omega Jun 2024Increasing evidence indicates that peripheral blood vessels play a pivotal role in regulating tumor growth with the presence of new blood vessels facilitating tumor...
Increasing evidence indicates that peripheral blood vessels play a pivotal role in regulating tumor growth with the presence of new blood vessels facilitating tumor growth and metastasis. Nevertheless, the impact of specific molecule-mediated angiogenesis on the tumor immune microenvironment (TIME) and individual prognosis of uterine corpus endometrial carcinoma (UCEC) remains uncertain. The transcriptome information on 217 prognostic angiogenesis-related genes was integrated, and the angiogenesis patterns of 506 UCEC patients in The Cancer Genome Atlas (TCGA) cohort were comprehensively evaluated. We identified five angiogenic subtypes, namely, EC1, EC2, EC3, EC4, and EC5, which differed significantly in terms of prognosis, clinicopathological features, cancer hallmarks, genomic mutations, TIME patterns, and immunotherapy responses. Additionally, an angiogenesis-related prognostic risk score (APRS) was constructed to enable an individualized comprehensive evaluation. In multiple cohorts, APRS demonstrated a powerful predictive ability for the prognosis of UCEC patients. Likewise, APRS was confirmed to be associated with clinicopathological features, genomic mutations, cancer hallmarks, and TIME patterns in UCEC patients. The predictability of APRS for immune checkpoint inhibitor (ICI) therapy was also salient. Subsequently, the expression levels of four angiogenesis-related hub genes were verified by qRT-PCR, immunohistochemistry, and single-cell sequencing data analysis. The effects of four representative genes on angiogenesis were validated by Wound-Healing and Transwell assays, tube formation assay in vitro, and tumor xenograft model in vivo. This study proffered a new classification of UCEC patients based on angiogenesis. The established APRS may contribute to individualized prognosis prediction and immunotherapy selections that are better suited for UCEC patients.
PubMed: 38911819
DOI: 10.1021/acsomega.4c03034 -
Veterinary World May 2024Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been... (Review)
Review
Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been described in breast, urinary, colorectal, prostate, and lung cancers as being involved in tumor initiation, promotion, progression, angiogenesis, and immunosuppression. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for several medical conditions to not only decrease pain and fever but also reduce inflammation by inhibiting COX and its product synthesis. To date, significant efforts have been made to better understand and clarify the interplay between cancer development, inflammation, and NSAIDs with a view toward addressing their potential for cancer management. This review provides readers with an overview of the potential use of NSAIDs and selective COX-2 inhibitors for breast cancer treatment, highlighting pre-clinical in vitro and in vivo studies employed to evaluate the efficacy of NSAIDs and their use in combination with other antineoplastic drugs.
PubMed: 38911075
DOI: 10.14202/vetworld.2024.1052-1072 -
Scientific Reports Jun 2024Angiogenesis is a key process for the proliferation and metastatic spread of cancer cells. Anti-angiogenic peptides (AAPs), with the capability of inhibiting...
Angiogenesis is a key process for the proliferation and metastatic spread of cancer cells. Anti-angiogenic peptides (AAPs), with the capability of inhibiting angiogenesis, are promising candidates in cancer treatment. We propose AAPL, a sequence-based predictor to identify AAPs with machine learning models of improved prediction accuracy. Each peptide sequence was transformed to a vector of 4335 numeric values according to 58 different feature types, followed by a heuristic algorithm for feature selection. Next, the hyperparameters of six machine learning models were optimized with respect to the feature subset. We considered two datasets, one with entire peptide sequences and the other with 15 amino acids from peptide N-termini. AAPL achieved Matthew's correlation coefficients of 0.671 and 0.756 for independent tests based on the two datasets, respectively, outperforming existing predictors by a range of 5.3% to 24.6%. Further analyses show that AAPL yields higher prediction accuracy for peptides with more hydrophobic residues, and fewer hydrophilic and charged residues. The source code of AAPL is available at https://github.com/yunzheng2002/Anti-angiogenic .
Topics: Machine Learning; Angiogenesis Inhibitors; Peptides; Algorithms; Amino Acid Sequence; Humans
PubMed: 38909149
DOI: 10.1038/s41598-024-65062-9 -
Cell Communication and Signaling : CCS Jun 2024Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating...
Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.
Topics: Humans; Animals; Human Umbilical Vein Endothelial Cells; Mice; Mitochondria; DNA-Directed RNA Polymerases; Diabetic Retinopathy; Mice, Inbred C57BL; Cell Proliferation; Neovascularization, Pathologic; Male; Neovascularization, Physiologic; Cell Movement; Apoptosis; Angiogenesis
PubMed: 38907279
DOI: 10.1186/s12964-024-01712-9 -
BMC Ophthalmology Jun 2024Retinopathy of prematurity (ROP) is a proliferative disorder of the developing retina. Intravitreal bevacizumab injection (IVB) is an emerging treatment for severe forms...
BACKGROUND
Retinopathy of prematurity (ROP) is a proliferative disorder of the developing retina. Intravitreal bevacizumab injection (IVB) is an emerging treatment for severe forms of ROP, which does not restrict the visual field in comparison to laser therapy. The present study aimed to determine and evaluate the risk factors for ROP recurrence following IVB injection.
MATERIALS AND METHODS
In this retrospective study, 98 eyes of 49 infants with ROP who had received IVB injections as the primary treatment for type 1 ROP are included.
RESULTS
Fifty-four eyes (55.1%) had aggressive retinopathy of prematurity (A-ROP), and forty-four (44.9%) had Stage III Plus ROP in Zone II. ROP recurred in 13 eyes (13.26%) of 8 infants. The mean period between IVB and the ROP recurrence was 8.08 (95% CI:5.32-10.83) weeks. The infants who had ROP recurrence had lower birth weight (P value = 0.002), lower postmenstrual age at IVB injection (P value = 0.001), lower IVB injection gap period from birth (P value = 0.044), higher oxygen therapy requirement rate after IVB injection (P value < 0.001, OR:19.0) and higher oxygen therapy duration (P value = 0.006). The ROP severity, gestational age at birth, and diet were not statistically different between the recurrence and complete regression groups. Out of 13 eyes treated with laser photocoagulation because of ROP relapse, macula dragging occurred in one eye, and all the cases met the complete regression.
CONCLUSION
Low birth weight and oxygen therapy are the most important risk factors for ROP relapse, which requires meticulous oxygen treatment guidelines for premature infants.
Topics: Humans; Retinopathy of Prematurity; Bevacizumab; Intravitreal Injections; Retrospective Studies; Angiogenesis Inhibitors; Female; Male; Recurrence; Infant, Newborn; Gestational Age; Vascular Endothelial Growth Factor A; Risk Factors; Infant; Follow-Up Studies; Infant, Premature
PubMed: 38907228
DOI: 10.1186/s12886-024-03528-0 -
Indian Journal of Ophthalmology Jul 2024
Comparative Study
Topics: Humans; Intravitreal Injections; Administration, Oral; Rifampin; Central Serous Chorioretinopathy; Vascular Endothelial Growth Factor A; Propranolol; Angiogenesis Inhibitors; Adrenergic beta-Antagonists
PubMed: 38905466
DOI: 10.4103/IJO.IJO_2774_23 -
Frontiers in Immunology 2024Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of...
Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity.
Topics: Psoriasis; Animals; Keratinocytes; Humans; Mice; Cell Proliferation; Granzymes; Interleukin-23; Inflammation; Imiquimod; Disease Models, Animal; Mice, Knockout; Female; Male; Mice, Inbred C57BL
PubMed: 38903528
DOI: 10.3389/fimmu.2024.1398120 -
Frontiers in Immunology 2024Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other... (Review)
Review
Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immune-mediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy.
Topics: Female; Humans; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Mixed Connective Tissue Disease; Ovarian Neoplasms; Purpura, Thrombocytopenic, Idiopathic
PubMed: 38903494
DOI: 10.3389/fimmu.2024.1382964 -
Nature Communications Jun 2024Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that...
Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.
Topics: Animals; Acid Sensing Ion Channels; Female; Mice, Knockout; Psoriasis; Mice; Calcitonin Gene-Related Peptide; Sensory Receptor Cells; Skin; Imiquimod; Mice, Inbred C57BL; Disease Models, Animal; Inflammation; Neurogenic Inflammation; Humans; Nociceptors; Interleukin-23
PubMed: 38902277
DOI: 10.1038/s41467-024-49577-3 -
Nature Communications Jun 2024While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown....
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34 progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
Topics: Humans; Lenalidomide; Myelodysplastic Syndromes; Hematopoietic Stem Cells; Antigens, CD34; Chromosome Deletion; Chromosomes, Human, Pair 5; Single-Cell Analysis; Male; Female; Aged; Gene Regulatory Networks; Middle Aged; Hematopoiesis; Transcriptome; Aged, 80 and over; RNA-Seq; Gene Expression Profiling
PubMed: 38902243
DOI: 10.1038/s41467-024-49529-x