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Cells May 2024The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs)...
The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their migration to the vasculature. In gray horse melanoma, epithelial-mesenchymal transition (EMT) is poorly understood, prompting us to address MP expression in lesions versus intact skin by transcriptome analyses and the immunofluorescence staining (IF) of gray horse tumor tissue and primary melanoma cells. RNAseq revealed the deregulation of several MPs in gray horse melanoma and, notably, a 125-fold upregulation of matrix metalloproteinase 1 (MMP1) that was further confirmed by RT-qPCR from additional tumor material. The IF staining of melanoma tissue versus intact skin for MMP1 and tumor marker S100 revealed MMP1 expression in all lesions. The co-expression of S100 was observed at different extents, with some tumors scoring S100-negative. The IF staining of primary tumor cells explanted from the tumors for MMP1 showed that the metalloproteinase is uniformly expressed in the cytoplasm of 100% of tumor cells. Overall, the presented data point to MP expression being deregulated in gray horse melanoma, and suggest that MMP1 has an active role in gray horse melanoma by driving EMT-mediated tumor cell dissemination via the degradation of the extracellular matrix. Whilst S100 is considered a reliable tumor marker in human MM, gray horse melanomas do not seem to regularly express this protein.
Topics: Animals; Melanoma; Horses; Gene Expression Regulation, Neoplastic; Matrix Metalloproteinase 1; Epithelial-Mesenchymal Transition; Skin Neoplasms; Cell Line, Tumor; Metalloproteases; Humans
PubMed: 38891088
DOI: 10.3390/cells13110956 -
Communications Medicine Jun 2024Sepsis from infection is a global health priority and clinical trials have failed to deliver effective therapeutic interventions. To address complicating heterogeneity...
BACKGROUND
Sepsis from infection is a global health priority and clinical trials have failed to deliver effective therapeutic interventions. To address complicating heterogeneity in sepsis pathobiology, and improve outcomes, promising precision medicine approaches are helping identify disease endotypes, however, they require a more complete definition of sepsis subgroups.
METHODS
Here, we use RNA sequencing from peripheral blood to interrogate the host response to sepsis from participants in a global observational study carried out in West Africa, Southeast Asia, and North America (N = 494).
RESULTS
We identify four sepsis subtypes differentiated by 28-day mortality. A low mortality immunocompetent group is specified by features that describe the adaptive immune system. In contrast, the three high mortality groups show elevated clinical severity consistent with multiple organ dysfunction. The immunosuppressed group members show signs of a dysfunctional immune response, the acute-inflammation group is set apart by molecular features of the innate immune response, while the immunometabolic group is characterized by metabolic pathways such as heme biosynthesis.
CONCLUSIONS
Our analysis reveals details of molecular endotypes in sepsis that support immunotherapeutic interventions and identifies biomarkers that predict outcomes in these groups.
PubMed: 38890515
DOI: 10.1038/s43856-024-00542-7 -
Molecular Diagnosis & Therapy Jul 2024Apoptosis, or programmed cell death, maintains tissue homeostasis by eliminating damaged or unnecessary cells. However, cells can evade this process, contributing to... (Review)
Review
Apoptosis, or programmed cell death, maintains tissue homeostasis by eliminating damaged or unnecessary cells. However, cells can evade this process, contributing to conditions such as cancer. Escape mechanisms include anoikis, mitochondrial DNA depletion, cellular FLICE inhibitory protein (c-FLIP), endosomal sorting complexes required for transport (ESCRT), mitotic slippage, anastasis, and blebbishield formation. Anoikis, triggered by cell detachment from the extracellular matrix, is pivotal in cancer research due to its role in cellular survival and metastasis. Mitochondrial DNA depletion, associated with cellular dysfunction and diseases such as breast and prostate cancer, links to apoptosis resistance. The c-FLIP protein family, notably CFLAR, regulates cell death processes as a truncated caspase-8 form. The ESCRT complex aids apoptosis evasion by repairing intracellular damage through increased Ca2+ levels. Antimitotic agents induce mitotic arrest in cancer treatment but can lead to mitotic slippage and tetraploid cell formation. Anastasis allows cells to resist apoptosis induced by various triggers. Blebbishield formation suppresses apoptosis indirectly in cancer stem cells by transforming apoptotic cells into blebbishields. In conclusion, the future of apoptosis research offers exciting possibilities for innovative therapeutic approaches, enhanced diagnostic tools, and a deeper understanding of the complex biological processes that govern cell fate. Collaborative efforts across disciplines, including molecular biology, genetics, immunology, and bioinformatics, will be essential to realize these prospects and improve patient outcomes in diverse disease contexts.
Topics: Humans; Apoptosis; Neoplasms; Endosomal Sorting Complexes Required for Transport; Animals; CASP8 and FADD-Like Apoptosis Regulating Protein
PubMed: 38890247
DOI: 10.1007/s40291-024-00718-w -
Surgical Case Reports Jun 2024Gerbode defect is an unusual abnormal communication between the left ventricle and the right atrium and is a serious complication of aortic infective endocarditis. Group...
BACKGROUND
Gerbode defect is an unusual abnormal communication between the left ventricle and the right atrium and is a serious complication of aortic infective endocarditis. Group B Streptococcus is an uncommon cause of infective endocarditis and has a markedly destructive effect on valvular tissue. Acute fistulation between the left ventricle and the right atrium associated with this form of infective endocarditis is a life-threatening, aggressive complication that often requires urgent surgical intervention. However, the identification of actual communication is often extremely difficult. Herein, we describe an unusual case of Gerbode defect resulting from Group B Streptococcus infective endocarditis and discuss the issues surrounding such a rare cardiac defect and such an infection.
CASE PRESENTATION
A 60-year-old man with underlying uncontrolled diabetes mellitus underwent endoscopic retrograde biliary drainage for acute cholangitis. On the 10th postoperative day, the patient developed multiple acute cerebral embolisms. Transthoracic echocardiography demonstrated severe aortic regurgitation and a large mobile vegetation near the tricuspid annulus. No obvious fistula between the left ventricle and the right atrium could be demonstrated. The blood culture examination was positive for Group B Streptococcus. The patient was diagnosed with Group B Streptococcus infective endocarditis, and antibiotic therapy was initiated. Transesophageal echocardiogram performed after referral to our hospital confirmed detachment of the right coronary cusp of the aortic valve from the annulus and an abnormal cavity immediately below the right coronary cusp. Color Doppler imaging finally revealed systolic blood flows from the left ventricle into the right atrium through the cavity. Therefore, we diagnosed the patient with Gerbode defect resulting from Group B Streptococcus infective endocarditis. In addition to aortic valve replacement, defect closure and left ventricular outflow tract repair were successfully performed urgently for severely complicated and uncommon infective endocarditis. The patient was uneventfully discharged without any complications.
CONCLUSIONS
We reported successful surgical treatment of unusual active IE and Gerbode defect caused by GBS. Careful preoperative echocardiographic work-up is imperative for accurate early diagnosis and successful repair.
PubMed: 38890183
DOI: 10.1186/s40792-024-01943-5 -
Beilstein Journal of Nanotechnology 2024The mechanism by which insects achieve attachment and locomotion across diverse substrates has long intrigued scientists, prompting extensive research on the functional...
The mechanism by which insects achieve attachment and locomotion across diverse substrates has long intrigued scientists, prompting extensive research on the functional morphology of attachment pads. In stick insects, attachment and locomotion are facilitated by two distinct types of smooth cuticular attachment pads: the primary adhesion force-generating arolium and the friction force-generating euplantulae. They are both supported by an adhesive secretion delivered into the interspace between the attachment pads and the substrate. In this study, we analysed and compared internal morphology, material composition and ultrastructure, as well as the transportation pathways in both adhesive organs in the stick insect using scanning electron microscopy, micro-computed tomography, light microscopy, and confocal laser scanning microscopy. Our observations revealed structural differences between both attachment pads, reflecting their distinct functionality. Furthermore, our results delineate a potential pathway for adhesive secretions, originating from exocrine epidermal cells and traversing various layers before reaching the surface. Within the attachment pad, the fluid may influence the viscoelastic properties of the pad and control the attachment/detachment process. Understanding the material composition of attachment pads and the distribution process of the adhesive secretion can potentially aid in the development of more effective artificial attachment systems.
PubMed: 38887530
DOI: 10.3762/bjnano.15.52 -
BMC Ophthalmology Jun 2024
PubMed: 38886683
DOI: 10.1186/s12886-024-03525-3 -
PloS One 2024Photodynamic venous occlusion is a commonly accepted method for establishing mouse models of retinal vein occlusion (RVO). However, existing model parameters do not...
Photodynamic venous occlusion is a commonly accepted method for establishing mouse models of retinal vein occlusion (RVO). However, existing model parameters do not distinguish between acute and chronic RVO subtypes. Large variations in laser energy seem to correlate with fluctuating retinopathy severity and high rates of venous recanalization during the acute phase, along with the variable levels of retinal perfusion during the chronic phase. After optimizing the modeling procedure and defining success and exclusion criteria, laser energy groups of 80mW, 100mW, and 120mW were established. Multimodal imaging confirmed that higher energy levels increased the incidence of retinal cystoid edema and intraretinal hemorrhage, exacerbated the severity of exudative retinal detachment, and reduced the venous recanalization rate. For the acute model, 100mW was considered an appropriate parameter for balancing moderate retinopathy and venous recanalization. Continuous imaging follow-up revealed that day 1 after RVO was the optimal observation point for peaking of retinal thickness and intensive occurrence of retinal cystic edema and intraretinal hemorrhage. After excluding the influence of venous recanalization on retinal thickness, acute retinal edema demonstrated a positive response to standard anti-vascular endothelial growth factor therapy, validating the clinical relevance of the acute RVO model for further study in pathogenic mechanisms and therapeutic efficacy. For the chronic model, the 120mW parameter with the lowest venous recanalization rate was applied, accompanied by an increase in both photocoagulation shots and range to ensure sustained vein occlusion. Imaging follow-up clarified non-ischemic retinopathy characterized by tortuosity and dilation of the distal end, branches, and adjacent veins of the occluded vein. These morphological changes are quantifiable and could be combined with electrophysiological functional assessment for treatment effectiveness evaluation. Moreover, the stable state of venous occlusion may facilitate investigations into response and compensation mechanisms under conditions of chronic retinal hypoperfusion.
Topics: Retinal Vein Occlusion; Animals; Disease Models, Animal; Mice; Acute Disease; Chronic Disease; Lasers; Mice, Inbred C57BL; Male; Tomography, Optical Coherence; Retina
PubMed: 38885229
DOI: 10.1371/journal.pone.0305741 -
Journal of Pharmacy & Bioallied Sciences Apr 2024Descemet membrane endothelial keratoplasty (DMEK) has been utilized more frequently during recent years to treat penetrating keratoplasty (PKP) graft failures. The...
BACKGROUND
Descemet membrane endothelial keratoplasty (DMEK) has been utilized more frequently during recent years to treat penetrating keratoplasty (PKP) graft failures. The perioperative evaluation technique of anterior segment optical coherence tomography (AS-OCT) is increasingly significant. Our goal is to discuss DMEK surgical and clinical for subsequent PKP graft failure, along with significant surgical modifications and adjustments in accordance with preoperative assessment utilizing AS-OCT.
MATERIALS AND METHODS
Patients' records who performed DMEK for PKP failure were retrospectively reviewed. Demographic information, PKP graft size determined by postoperative problems, corneal donor endothelial cell density (ECD), AS-OCT, central pachymetry, visual acuity (VA) evaluated in Snellen units, intraoperative surgical procedure modifications, and postoperative ECD were all included in the data collection.
RESULTS
The observation was conducted with 16 patients with 16 eyes, nine males and seven females. The observation period is 18 months. DMEK was performed at an average age of 63. Preoperative AS-OCT was performed on all patients, and based on cases, surgical plans were created. Before processing DMEK, the mean VA is 0.04, and central pachymetry is 685 m. They improved considerably to 0.3 ( value = 0.001) and 542 m ( value = 0.008) at the most recent follow-up. About 93.75% of the grafts were adhered to after the procedure. Late decompensation caused a 6.25% graft failure rate. Graft detachment rates and cases requiring rebubble rates were respectively 18.75%.
CONCLUSION
In DMEK for failed PKP, a good case-specific preoperative assessment by AS-OCT is essential. As a result, it relies on developing a surgical strategy that can improve surgical outcomes, lower the risk of complications, and quicken visual recovery.
PubMed: 38882795
DOI: 10.4103/jpbs.jpbs_876_23 -
Journal of Pharmacy & Bioallied Sciences Apr 2024Matrix metalloproteinase-1 (MMP-1) plays a pivotal role in the pathogenesis of periodontal diseases, particularly periodontitis, by virtue of its collagenolytic activity... (Review)
Review
Matrix metalloproteinase-1 (MMP-1) plays a pivotal role in the pathogenesis of periodontal diseases, particularly periodontitis, by virtue of its collagenolytic activity targeting collagen type I, the primary component of periodontal tissues. This review abstract elucidates the intricate involvement of MMP-1 in periodontal tissue homeostasis and its dysregulation in disease states. Elevated MMP-1 levels, observed in gingival tissues and crevicular fluid of individuals with periodontitis, correlate with the degradation of collagen fibers within the periodontium. This degradation contributes to the detachment of teeth from surrounding tissues and exacerbates alveolar bone resorption, hallmark features of periodontal breakdown. Therapeutically, targeting MMP-1 activity emerges as a promising strategy, prompting ongoing research into MMP inhibitors and host modulation therapies. Understanding MMP-1's nuanced role in periodontal diseases paves the way for personalized treatment approaches and holds promise in reshaping periodontal disease management for improved patient outcomes and periodontal health.
PubMed: 38882751
DOI: 10.4103/jpbs.jpbs_1249_23 -
Ocular Oncology and Pathology Jun 2024Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong...
INTRODUCTION
Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension.
CASE PRESENTATIONS
In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients' IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy.
DISCUSSION/CONCLUSION
This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.
PubMed: 38882021
DOI: 10.1159/000535427