Growth Factor Antagonist Research Articles

Setting a Pig Model of Crescentic Glomerulonephritis and Testing a Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) Antagonist as a New Treatment

Setting a Pig Model of Crescentic Glomerulonephritis and Testing a Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) Antagonist as a New Treatment

Effect of Dopamine as a Vascular Endothelial Growth Factor Antagonist on the Development of Acute Lung Injury in Sepsis Patients.

Sepsis is a dysregulated host immune response stemming from a systemic inflammatory response to microbial invasion, encompassing bacteria, viruses, and other pathogens. The vascular endothelial growth factor (VEGF) was initially identified for its potent induction of endothelial permeability. Studies have proposed a therapeutic role of dopamine in mitigating VEGF-induced permeability, shedding light on its potential in acute respiratory distress syndrome (ARDS) management. To determine the effect of dopamine as an inhibitor of VEGF and to prevent the progression of sepsis to acute lung injury (ALI) and ARDS. A total of 154 critical care unit patients with a diagnosis of sepsis were randomized into two groups:Group I (control group) and Group II (Study group). Both received standard treatment, as per ICU protocol. In addition, the study group (Group II) received a dopamine infusion of 2 micrograms/kg/min. Baseline routine investigation, procalcitonin, and chest X-ray were done. Day one and day seven blood samples were stored for analysis of VEGF levels. Murray's score and sequential organ failure assessment (SOFA) score (organ dysfunction) were calculated from day one to day seven. VEGF levels on day seven were significantly lower in the study group compared to the control group (p<0.05). The PaO2/FiO2 ratio at day seven was significantly increased in the study group than in the control group, indicating an improvement in oxygenation status in the study group. There was a mean ICU stay of 9.3 days in the study group versus 11.6 days in the control group (p<0.05). The SOFA score showed a significant improvement in the study group from day five onwards, indicating a therapeutic effect of dopamine on organ dysfunction in sepsis. Dopamine reduces VEGF and lung injury mediated by increased endothelial permeability.

Molecular analysis of a self-organizing signaling pathway for Xenopus axial patterning from egg to tailbud

Xenopus embryos provide a favorable material to dissect the sequential steps that lead to dorsal-ventral (D-V) and anterior-posterior (A-P) cell differentiation. Here, we analyze the signaling pathways involved in this process using loss-of-function and gain-of-function approaches. The initial step was provided by Hwa, a transmembrane protein that robustly activates early β-catenin signaling when microinjected into the ventral side of the embryo leading to complete twinned axes. The following step was the activation of Xenopus Nodal-related growth factors, which could rescue the depletion of β-catenin and were themselves blocked by the extracellular Nodal antagonists Cerberus-Short and Lefty. During gastrulation, the Spemann-Mangold organizer secretes a cocktail of growth factor antagonists, of which the BMP antagonists Chordin and Noggin could rescue simultaneously D-V and A-P tissues in β-catenin-depleted embryos. Surprisingly, this rescue occurred in the absence of any β-catenin transcriptional activity as measured by β-catenin activated Luciferase reporters. The Wnt antagonist Dickkopf (Dkk1) strongly synergized with the early Hwa signal by inhibiting late Wnt signals. Depletion of Sizzled (Szl), an antagonist of the Tolloid chordinase, was epistatic over the Hwa and Dkk1 synergy. BMP4 mRNA injection blocked Hwa-induced ectopic axes, and Dkk1 inhibited BMP signaling late, but not early, during gastrulation. Several unexpected findings were made, e.g., well-patterned complete embryonic axes are induced by Chordin or Nodal in β-catenin knockdown embryos, dorsalization by Lithium chloride (LiCl) is mediated by Nodals, Dkk1 exerts its anteriorizing and dorsalizing effects by regulating late BMP signaling, and the Dkk1 phenotype requires Szl.

New therapeutic strategies in osteoarthritis

Osteoarthritis (OA) is the most prevalent arthritis-type and is a major contributor to chronic joint pain, impaired physical function, and limited mobility. By the end of 2020, a total of 595 million, equal to 7·6% of the global population, had OA; this figure is expected to rise exponentially by 2050. Even while the disorder's intricate pathophysiology is starting to appear intelligible, we are yet to have a cure for the disorder. OA is typically managed with traditional palliative measures, such as topical and systemic analgesics, including non-steroidal anti-inflammatory drugs, therapeutic exercise, and braces. Sometimes, intra-articular glucocorticoids, viscosupplementation, or regenerative interventions provide short-term pain relief and functional improvement; some may require arthroplasty. Researchers continue their efforts to unveil a new therapeutic target to be effective in OA that modifies symptoms and arrests disease progression as well. In the present literature review, insights into new therapeutic strategies in OA, for example, liposome-based dexamethasone, microspore-based triamcinolone, nerve growth factor antagonist, anti-ADAMTS-5 (A Disintegrin And Metalloproteinase Thrombospoidin Motifs - 5), pentosan polysulfate sodium, allogeneic stem cells, C-C chemokine receptor type-4 (CCR4) ligand 17 inhibitor, Wnt-signaling inhibitor, and anti-obesity medications are provided.

Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study

Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to anti-VEGF were assigned to four cohorts differing by ixo-vec dose (2×1011 vs 6×1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6×1011 dose group and in 7 participants in the 2×1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2×1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2×1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6×1011 vg/eye cohorts. Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions. Adverum Biotechnologies.

Head organizer: Cerberus and IGF cooperate in brain induction in Xenopus embryos

Neural induction by cell-cell signaling was discovered a century ago by the organizer transplantations of Spemann and Mangold in amphibians. Spemann later found that early dorsal blastopore lips induced heads and late organizers trunk-tail structures. Identifying region-specific organizer signals has been a driving force in the progress of animal biology. Head induction in the absence of trunk is designated archencephalic differentiation. Two specific head inducers, Cerberus and Insulin-like growth factors (IGFs), that induce archencephalic brain but not trunk-tail structures have been described previously. However, whether these two signals interact with each other had not been studied to date and was the purpose of the present investigation. It was found that Cerberus, a multivalent growth factor antagonist that inhibits Nodal, BMP and Wnt signals, strongly cooperated with IGF2, a growth factor that provides a positive signal through tyrosine kinase IGF receptors that activate MAPK and other pathways. The ectopic archencephalic structures induced by the combination of Cerberus and IGF2 are of higher frequency and larger than either one alone. They contain brain, a cyclopic eye and multiple olfactory placodes, without trace of trunk structures such as notochord or somites. A dominant-negative secreted IGF receptor 1 blocked Cerberus activity, indicating that endogenous IGF signals are required for ectopic brain formation. In a sensitized embryonic system, in which embryos were depleted of β-catenin, IGF2 did not by itself induce neural tissue while in combination with Cerberus it greatly enhanced formation of circular brain structures expressing the anterior markers Otx2 and Rx2a, but not spinal cord or notochord markers. The main conclusion of this work is that IGF provides a positive signal initially uniformly expressed throughout the embryo that potentiates the effect of an organizer-specific negative signal mediated by Cerberus. The results are discussed in the context of the history of neural induction.

Study of aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema

BackgroundThe aim was to study aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema (DMO).MethodsThis was a case-control prospective study conducted on 2 groups: 25 eyes of 22 (11 females) patients seeking treatment for DMO as patients group, and 10 eyes of 10 (4 females) cataract patients as a control group. Aqueous humour was aspirated before intravitreal injection (patients’ group) or cataract surgery (control group). Inflammatory mediators in aqueous humour were measured using a multiplex bead immunoassay kit of 27 pre-mixed cytokines.ResultsEotaxin, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleukin-8 (IL-8/CXCL8) were found significantly higher in patients’ group compared to control group (p = 0.043, 0.037, 0.001, 0.015 respectively). On the contrary, interferon-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CSF) were found significantly higher in control group than patients’ group (p = 0.003, 0.019 respectively). Basic fibroblast growth factor (Basic-FGF/FGF-2) and interleukin-1 receptor antagonist (IL-1ra) were found higher (but not statistically significant) in controls (p = 0.100 and 0.070 respectively). Additionally, a negative and significant correlation was found between Eotaxin level in aqueous humour and central macular thickness.ConclusionsSome mediators might be implicated in the pathogenesis of DMO either augmenting or suppressing role. Eotaxin, IP-10, MCP-1 and IL-8 might have a role in cases not responding to standard anti-vascular endothelial growth factor (VEGF) therapy. IL-1ra might have a protective role; therefore, the effectiveness of intravitreal injection of IL-1ra homologue needs to be studied in future clinical trials.

Vascular endothelial growth factor antagonist peptides inhibit tumor growth and metastasis in breast cancer through repression of c-src and STAT3 genes.

Breast cancer is one of the most decisive causes of cancer death in women worldwide. Cancer progression and tumor metastasis depend on angiogenesis. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2) are critically required for tumor angiogenesis. Src is involved in many of the VEGF-mediated pathways. The VEGFRs activate Src via different mechanisms. Given that Src activates STAT3 (signal transducers and activators of transcription) repressing apoptosis and promoting the cell cycle, it may be an important object for cancer treatment. A series of VEGF antagonistic peptides, referred to as VGB 1,3 and 4, were designed to bind and block both VEGFR1 and VEGFR2 inhibiting the proliferation of different tumoral cells. We investigated c-Src and STAT3 gene expression changes in murine 4T1 tumors treated by the VGBs. The treated group received 1 and 10mgkg-1 of the peptides, while the control mice received PBS, intraperitoneally for two weeks. Both of the groups underwent a resection of breast tissue 14 days after treatment. The results of qRT-PCR showed that the expression levels of c-Src and STAT3 genes were significantly decreased, in a dose-dependent manner, after treatment with the different types of VEGF antagonist peptides, compared to the control groups (P < 0.05). The groups treated with 1mgkg-1 of all three types of VGB showed decreased expression of c-Src and STAT3 less than the groups receiving 10mgkg-1 of the anti-angiogenic peptides. In conclusion, peptides VGB1, 3, and 4, could be effective therapeutic molecules in breast cancer by inhibiting angiogenesis and progression of the disease.

The role of epidermal growth factor and cholinergic receptor agonists and antagonists in MAPK signal transduction in K562 cells

Objective: Muscarinic receptors (M1-M5) are members of the G protein-coupled receptor superfamily and are effective in physiological&#x0D; functions through G proteins. Recent studies suggested that cholinergic receptors mediate cellular activities in hematopoietic cells.&#x0D; The aim of this study was to investigate the potential role of mitogen-activated protein kinases (MAPK) signaling extracellular signalregulated&#x0D; kinases 1 and 2 (ERK1/2)/phosphorylated ERK1/ (pERK1/2) pathways in chronic myeloid leukemia (K562) cells.&#x0D; Materials and Methods: Chronic myeloid leukemia cells were cultured. Cells were incubated in the presence of muscarinic receptor&#x0D; agonist, antagonist and epidermal growth factor (EGF). To detect MAPK activation, ERK/pERK protein expression levels were&#x0D; determined by western blot method techniques.&#x0D; Results: Our study results showed that cholinergic agents and EGFs affect the MAPK pathway in the human K562 cell line.&#x0D; Conclusion: Cholinergic and EGF receptors may affect the MAPK pathway in K562 cells.&#x0D; Conclusion: Cholinergic and EGF receptors may affect the MAPK pathway in K562 cells.

Efficacy of Intravitreal Bevacizumab in management of Chronic Central Serous Chorioretinopathy: A Meta-Analysis of Prospective Studies

Background Central serous chorioretinopathy (CSC) is described as a chorio-retinal disease, associated with the serous detachment of the neurosensory retina and/or retinal pigment epithelium (RPE) most commonly seen in the macular region. Aim of the Work To evaluate the efficacy of Bevacizumab, an intravitreal vascular endothelial growth factor antagonist, in treatment of chronic central serous chorioretinopathy by conducting a Meta-Analysis of the available data from prospective studies. Materials and Methods A comprehensive literature search was conducted using the databases Google scholar, PubMed, MEDS, web of science, EMBASE and Cochrane Library for published studies till June 2021.This meta-analysis included eight studies. They were prospective studies, six of them were case series and the remaining two were randomised controlled trials (RCTs). 105 patients with chronic CSC (105 eyes) participated in these studies. Results This study demonstrated a statistically significant change in the mean of best corrected visual acuity (BCVA) improvement and central macular thickness (CMT) reduction when comparing the baseline to one- three- and six-month follow-ups after the injection. No adverse effects were reported in any of the included studies. Conclusion Intra-vitreal injection of bevacizumab is an excellent alternative and conceivable treatment among currently available treatment options for chronic or recurrent or refractory cases of central serous chorioretinopathy.

Immunotherapy for Advanced Hepatocellular Carcinoma-a Large Tertiary Center Experience

IntroductionCombination of immune-checkpoint inhibitor (ICI) and vascular endothelial growth factor (VEGF) antagonist has become the first line systemic treatment for advanced hepatocellular carcinoma (HCC). However, two-thirds of patients do not respond to ICI-based treatments and biomarkers for response remain elusive. MethodsPatients with advanced HCC who received Atezolizumab/Bevacizumab combination or Nivolumab during 2016-2022 were identified in our Liver Cancer Database. Retrospective review of their clinical data was performed to investigate parameters that could be predictive of immunotherapy response. Results96 patients received Atezolizumab/Bevacizumab (n=60) or Nivolumab (n=36). Median age at diagnosis was 67.1 years. 70 patients had received treatment and 26 patients were treatment naïve before starting immunotherapy. Mean pre-treatment AFP was 9780.7 (±32035) ng/mL. Confirmed objective response (complete or partial) was seen in 29% of the population (n=27). Disease remained stable in 12% (n=11) and progressed in 60% (n=56). On univariate analysis, pre-treatment AFP>400 ng/mL was associated with objective response (OR=4.5, 95% CI:1.7-11.9, p=0.0015), while white race (OR=0.35, 95% CI:0.13-0.92, p=0.030) and prior radiotherapy (OR=0.14, 95% CI:0.01-1.1, p=0.033) or systemic therapy with TKIs (OR=0.25, 95% CI:0.08-0.81, p=0.017) were associated with poor response. On multivariate analysis only AFP>400 ng/mL remained associated with response (OR=3.7, 95% CI:1.3-10.5, p=0.014). Overall survival (OS) at one and three years was 86% and 43% in responders, and 45% and 29% in non-responders, respectively. ConclusionIn our institutional experience, treatment naivety and pre-treatment AFP>400 ng/mL were associated with objective response. Prospective studies aimed at identifying factors associated with response to immunotherapy will aide patient selection.

Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion.

Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO. Adult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8. Both VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO. Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.

Inner Retinal Changes in Acute Experimental BRVO Treated With Bevacizumab or Triamcinolone Acetonide.

Apoptosis is a key process in neural degeneration associated with retinal vascular diseases. Vascular endothelial growth factor (VEGF) antagonists, including bevacizumab, are used to treat macular edema in these diseases. As VEGF has a critical role in the preservation of retinal neuronal cells, this study investigates the effects of bevacizumab on neural damage in a pig model of branch retinal vein occlusion (BRVO) and compares it with triamcinolone acetonide (TA) which is reported to possess neuroprotective properties. Thirty-six pigs had a photothrombotic BRVO in both eyes. Six pigs were injected with bevacizumab in one eye and TA in the fellow eye, then they were sacrificed, the eyes enucleated, and retinas processed at 2, 6, 10, and 20 days, respectively, together with three pigs (six eyes) BRVO only and three normal pigs (six eyes). Neuronal degeneration (apoptosis) and associated inner retinal changes were determined by terminal deoxyynuclotidyl transferase dUTP nick-end labeling (TUNEL), histology, and immunohistochemistry for macrophages. TUNEL labeling showed significantly higher apoptosis rates in the ganglion cell layer (GCL) and the inner nuclear layer (INL) in the bevacizumab-treated compared with the TA-treated retinas at 2, 10, and 20 day time points after occlusion (P < 0.05). Pyknotic cells were significantly higher in the GCL in bevacizumab-treated eyes at 6, 10, and 20 days and in the INL at 2 days compared to TA-treated retinas (P < 0.05). Macrophage infiltration was seen at all time points in both untreated and treated retinas with an absence of significance between bevacizumab- and TA-treated retinas (P > 0.05). Neurodegeneration in the BRVO acute phase is exacerbated by current standard treatments for BRVO. These results may have implications for the timing and treatment type. In the acute phase of BRVO, VEGF suppression with bevacizumab and to a lesser extent with triamcinolone exacerbates apoptosis in the inner retinal layers, which has implications for both the timing and choice of treatment.

Associations of soluble fms-like tyrosine kinase-1 with cardiovascular events and stroke in patients with atrial fibrillation and suspected or known coronary artery disease: the EXCEED-J study

Abstract Background Atrial fibrillation (AF) increases the risk of stroke. Soluble fms-like tyrosine kinase-1 (sFlt-1), a vascular endothelial growth factor (VEGF) antagonist, has been suggested as a marker of endothelial dysfunction, which are associated with both AF and coronary artery disease (CAD). Recently, we demonstrated that sFlt-1 is independently associated with major adverse cardiovascular (CV) events (MACE) in patients with suspected or known CAD. However, the prognostic utility of sFlt-1 in patients with AF remains unknown. Methods Using data from a multicenter, prospective cohort of 3255 patients with suspected or known CAD, we investigated whether AF modifies the prognostic utility of sFlt-1. Heparin-free serum levels of sFlt-1, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin-I, high-sensitivity C-reactive protein, cystatin C, neutrophil gelatinase-associated lipocalin, VEGF, and placental growth factor were measured in 324 patients with AF and 2931 patients without AF. The primary outcome was MACE defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, CV death, stroke, heart failure (HF) hospitalization, and coronary/peripheral artery revascularization. The biomarkers were natural log-transformed for use as continuous variables. Results After adjustment for potential clinical confounders including anticoagulant drug use, sFlt-1 was significantly associated with MACE (hazard ratio for 1 standard deviation increase [HR], 1.55; 95% confidence interval [CI], 1.14–2.08), CV death (HR, 1.68; 95% CI, 1.10–2.48), and stroke (HR, 1.89; 95% CI, 1.16–3.10), but not with all-cause death (HR, 1.32; 95% CI, 0.99–1.73), HF hospitalization (HR, 0.97; 95% CI, 0.73–1.25), or revascularization (HR, 0.99; 95% CI, 0.74–1.28) in patients with AF, whereas sFlt-1 was significantly associated with MACE (HR, 1.19; 95% CI, 1.02–1.37), all-cause death (HR, 1.19; 95% CI, 1.05–1.34), CV death (HR, 1.26; 95% CI, 1.03–1.48), and HF hospitalization (HR, 1.26; 95% CI, 1.11–1.42), but not with stroke (HR, 1.06; 95% CI, 0.81–1.33) or revascularization (HR, 1.01; 95% CI, 0.95–1.07) in patients without AF. Among other biomarkers, only VEGF was significantly associated with MACE (HR, 1.55; 95% CI, 1.02–2.44), and no biomarkers were significantly associated with CV death or stroke in patients with AF. sFlt-1 added incremental prognostic information for MACE (P=0.005 for net reclassification improvement [NRI], P=0.026 for integrated discrimination improvement [IDI]) and stroke (P=0.034 for NRI, P=0.018 for IDI), but not for CV death (P=0.021 for NRI, P=0.134 for IDI), to the model with potential clinical confounders in patients with AF. Conclusions sFlt-1 independently predicted MACE and stroke in patients with AF and suspected or known CAD. sFlt-1 may serve as a novel prognostic biomarker to stratify the risk of MACE and stroke in patients with AF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Labour Sciences Research Grant (2013-2014), AMED (2015-2017, Grant Number JP17ek0210008)

A retrospective, single-center cohort study on complications after dental extractions in patients taking biologic agents

Although biologic agents represent a growing class of therapeutics, little is known about how these agents affect the provision of dental treatment. This retrospective case-control study analyzed patients undergoing dental extraction treated with biologic agents from 2017 through 2020. Complications within 30 days postextraction were recorded. One-hundred twenty-one patients were treated during 147 encounters. Fifteen patients experienced complications during 16 encounters. Notable or excessive pain was most common (14/16; 88%). Patients who experienced complications were treated with 7 biologic agents: dulaglutide, belimumab, adalimumab, aflibercept, tofacitinib, ranibizumab, and ixekizumab. Complication after extraction-specifically, pain-was elevated for patients receiving aflibercept and ranibizumab. When grouped by class, complications were more common with vascular endothelial growth factor antagonism. The impact of biologics on the provision of and recovery after dental treatment remains unknown. Pain was most commonly reported. Patients treated with vascular endothelial growth factor antagonists experienced an elevated rate of complications. This study provides preliminary data on how patients taking biologic agents heal after dental extraction. It is limited by small sample sizes. Further work will build on this data to determine appropriate management of patients taking biologics in the dental setting.

In silico Activity and Target Prediction Analyses of Three Triazolothiadiazine Derivatives

Objective: Polypharmacology, interaction of one drug with multiple targets, emerged as an effective approach in drug discovery and development. Bioinformatics and cheminformatics methods are essential tools for determination of polypharmacological profiles of newly synthesized or known compounds and drugs. Previously, three novel triazolothiadiazine derivatives; 1h, 3c and 3h, have been shown to induce apoptosis and cause cell cycle arrest on liver cancer cells. The aim of this study is to find possible action mechanisms and potential targets for these three triazolothiadiazine derivatives, and to investigate their potential as new therapeutic agents by using computational methods. Materials and Methods: PASS software was used to identify biological activities and Swiss Target Prediction and BindingDB databases to predict potential targets for 1h, 3c and 3h. PDE4A, ALR and DUSP1 proteins were selected for molecular docking analysis following the protein modeling of the three proteins. Results: Activity prediction results show that 1h, 3c and 3h might have phosphatase and signal transduction pathway inhibitor, hepatocyte growth factor antagonist, anti-inflammatory and antifungal activities. These derivatives are predicted as inhibitors of several phosphodiesterases by activity and target prediction tools. Conclusion: Based on prediction and molecular docking results, it is proposed that these compounds may have therapeutic properties through new predicted targets.

Activated Serum Increases In Vitro Cellular Proliferation and Growth Factor Expression of Musculoskeletal Cells.

The purpose of this study was to investigate proteomic alteration that occurs to whole blood when converted to activated serum (AS) using an autologous thrombin system. This study further sought to evaluate the functional in vitro effect of AS on tenocytes, chondrocytes, subacromial bursal cells, and osteoblasts. The peptide/protein composition of AS was analyzed by liquid chromatography–mass spectrophotometry (LC-MS). The cell lines were treated with AS, and cellular proliferation was quantified 48 h after treatment. Platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), interleukin-1 beta (IL-1β), and interleukin-1 receptor antagonist (IL-1Ra) were quantified utilizing enzyme-linked immunosorbent assays (ELISAs). LC-MS identified 357 proteins across the AS and whole blood. Fifty-four of the proteins identified had significant differences between the relative protein abundance of the AS samples compared to whole blood. Treatment with AS in all cell lines significantly increased proliferation compared to control cells at 48 h. Increased PDGF, VEGF, and IGF-1 in all cell lines exposed to AS compared to the control (p < 0.05) were observed. These findings suggest that treatment with AS increases in vitro cellular proliferation and the release of growth factors that may play a role in tissue repair.

Evo-Devo of Urbilateria and its larval forms

Developmental biology has contributed greatly to evolutionary biology in the past century. With the discovery that vertebrates share Hox genes with Drosophila in 1984, it became apparent that all animals evolved from variations of an ancestral embryonic patterning genetic tool-kit. In the dorsal-ventral (D-V) axis, a fundamental experiment was the Spemann-Mangold organizer transplant performed in 1924. Almost a century later, D-V genes have been subjected to saturating molecular screens in Xenopus and extensive genetic screens in zebrafish. A network of secreted growth factor antagonists has emerged, and we review here in detail the Chordin/Tolloid/BMP pathway. Chordin establishes a morphogen gradient spanning the entire embryo that was present even in the cnidarian Nematostella. This ancient system was present in Urbilateria, the last common ancestor of the protostome and deuterostome bilateral animals. We suggest that Urbilateria had a complex life cycle with an adult benthic form on the sea bottom, and also a primary larval pelagic or planktonic phase to disperse the species in the marine milieu. Larvae with two rows of cilia beating in opposite directions to entrap food particles, an apical sensory organ, and a rudimentary eye, are present in many protostome and deuterostome phyla. Although the larval phase has been lost multiple times in evolution, and larvae can adopt traits present in their adult forms, the simplest explanation is that Urbilateria had a pelago-benthic life cycle. The use of conserved developmental patterning systems likely placed evolutionary constraints in the animal forms that evolved by natural selection.

Vascular endothelial growth factor (VEGF) and interleukin-1 receptor antagonist (IL-1Ra) as promising biomarkers for distinguishing active from latent tuberculosis in children and adolescents

Since distinguishing pulmonary (PTB) from latent tuberculosis (LTBI) in pediatric patients remains a challenge, we aimed to investigate the efficacy of immune mediators in diagnosing PTB and LTBI in this population. In this cross-sectional study performed with children and adolescents, serum levels of 20 biomarkers were assessed and data were analyzed according to age groups. We included 65 participants (PTB, n = 28 and LTBI, n = 37). Overall, levels of TNF-α, IL-1Ra, IL-6, IL-17A, VEGF, MMP-1, and procalcitonin were significantly higher (P < 0.05) in adolescents and children <10 years-old with PTB. Also, principal component analysis (PCA) showed that immune mediators were able to distinguish PTB from LTBI. VEGF and IL-1Ra presented the highest area under the curve (AUC) values, both separately (AUC 0.890 and 0.785) and combined (AUC 0.99). Taken together, we showed that VEGF and IL-1Ra are promising biomarkers to distinguish PTB from LTBI in pediatric patients, especially in children <5 years-old.

Prevalence of persistent avascular retina in untreated children with a history of retinopathy of prematurity screening

Persistent avascular retina (PAR) in prematurely born individuals may be a risk factor for late sequelae of retinopathy of prematurity (ROP), including retinal detachment in older childhood and adulthood. Although PAR has been associated with use of vascular endothelial growth factor antagonist therapy for treatment-requiring ROP, the prevalence of this finding in patients without prior ROP treatment is unknown. We performed a cross-sectional study to determine the prevalence of PAR in a cohort of patients 4-8 years of age who were screened for ROP in the neonatal intensive care unit and did not receive treatment. Patients were recruited from an existing population-based cohort and underwent ultra-widefield fluorescein angiography (UWFFA). UWFFA images of 43 eyes of 23 patients were evaluated. Average age at time of evaluation was 6.2 years. PAR was observed in 21 patients (91%). Thirteen eyes (30%) had PAR in zone II; 23 (53%), in zone III. Six eyes (14%) had abnormal vessels without clear PAR. These findings indicate a high prevalence of PAR in patients with a history of ROP screening without treatment.