Value of soluble fms-like tyrosine kinase 1 for predicting acute pancreatitis severity: a systematic review and meta-analysis

SUMMARY OBJECTIVE: The objective of this study was to explore the relationship between serum soluble fms-like tyrosine kinase 1 and the severity of acute pancreatitis and its diagnostic utility. METHODS: This study was carried out by searching Chinese and English literature from the establishment of the database to July 9, 2023, systematically, and assessing the quality and heterogeneity of the articles included. RESULTS: Thirteen studies with a total of 986 patients were included. Patients with severe acute pancreatitis showed higher levels of soluble fms-like tyrosine kinase 1 compared with mild acute pancreatitis [weighted mean difference=76.64 pg/mL, 95% confidence interval (95%CI 50.39-102.89, p<0.001)]. Soluble fms-like tyrosine kinase 1 predicted pooled sensitivity, specificity, and area under the curve were 79%, 74%, and 0.85 for severe acute pancreatitis, with some heterogeneity (I2>50% or p<0.05). In the subgroup analysis, cutoff >150 pg/mL was found to be a heterogeneous factor. CONCLUSION: Soluble fms-like tyrosine kinase 1 is a reliable tool for identifying acute pancreatitis severity, but only as a screening tool.

Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis.

Dopamine (DA) and dopamine agonists (DA-Ag) have shown antiangiogenic potential through the vascular endothelial growth factor (VEGF) pathway. They inhibit VEGF and VEGF receptor 2 (VEGFR 2) functions through the dopamine receptor D2 (D2R), preventing important angiogenesis-related processes such as proliferation, migration, and vascular permeability. However, few studies have demonstrated the antiangiogenic mechanism and efficacy of DA and DA-Ag in diseases such as cancer, endometriosis, and osteoarthritis (OA). Therefore, the objective of this review was to describe the mechanisms of the antiangiogenic action of the DA-D2R/VEGF-VEGFR 2 system and to compile related findings from experimental studies and clinical trials on cancer, endometriosis, and OA. Advanced searches were performed in PubMed, Web of Science, SciFinder, ProQuest, EBSCO, Scopus, Science Direct, Google Scholar, PubChem, NCBI Bookshelf, DrugBank, livertox, and Clinical Trials. Articles explaining the antiangiogenic effect of DA and DA-Ag in research articles, meta-analyses, books, reviews, databases, and clinical trials were considered. DA and DA-Ag have an antiangiogenic effect that could reinforce the treatment of diseases that do not yet have a fully curative treatment, such as cancer, endometriosis, and OA. In addition, DA and DA-Ag could present advantages over other angiogenic inhibitors, such as monoclonal antibodies.

Identification of VEGFR2 as the Histatin-1 receptor in endothelial cells.

Histatin-1 is a salivary peptide with antimicrobial and wound healing promoting activities, which was previously shown to stimulate angiogenesis in vitro and in vivo via inducing endothelial cell migration. The mechanisms underlying the proangiogenic effects of Histatin-1 remain poorly understood and specifically, the endothelial receptor for this peptide, is unknown. Based on the similarities between Histatin-1-dependent responses and those induced by the prototypical angiogenic receptor, vascular endothelial growth factor receptor 2 (VEGFR2), we hypothesized that VEGFR2 is the Histatin-1 receptor in endothelial cells. First, we observed that VEGFR2 is necessary for Histatin-1-induced endothelial cell migration, as shown by both pharmacological inhibition studies and siRNA-mediated ablation of VEGFR2. Moreover, Histatin-1 co-immunoprecipitated and co-localized with VEGFR2, associating spatial proximity between these proteins with receptor activation. Indeed, pulldown assays with pure, tagged and non-tagged proteins showed that Histatin-1 and VEGFR2 directly interact in vitro. Optical tweezers experiments permitted estimating kinetic parameters and rupture forces, indicating that the Histatin-1-VEGFR2 interaction is transient, but specific and direct. Sequence alignment and molecular modeling identified residues Phe26, Tyr30 and Tyr34 within the C-terminal domain of Histatin-1 as relevant for VEGFR2 binding and activation. This was corroborated by mutation and molecular dynamics analyses, as well as in direct binding assays. Importantly, these residues were required for Histatin-1 to induce endothelial cell migration and angiogenesis in vitro. Taken together, our findings reveal that VEGFR2 is the endothelial cell receptor of Histatin-1 and provide insights to the mechanism by which this peptide promotes endothelial cell migration and angiogenesis.

Effect of Intracanal Medicaments and Irrigants on the Release of Transforming Growth Factor Beta 1 and Vascular Endothelial Growth Factor from Cervical Root Dentin.

INTRODUCTION: This study aimed to evaluate (1) the effect of irrigating solutions and intracanal medicaments on the release of transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF) from cervical root dentin and (2) the effect of associating triple antibiotic paste (TAP) and calcium hydroxide paste (CH) with 2% chlorhexidine (CHX) on TGF-ß1 release. METHODS: First, 119 specimens from roots (cervical thirds) were obtained and were distributed into 5 groups: 2% CHX, 2.5% sodium hypochlorite, TAP, CH, and 10% EDTA by each growth factor (TGF-ß1 [n = 8] and VEGF [n = 8]). Then, specimens were distributed as follows (n = 13): TAP + 2% CHX, CH + 2% CHX, and 10% EDTA and treated with irrigating solutions and intracanal medicaments. After the treatments, the specimens were immersed in 10% EDTA (20 minutes), and the solution was analyzed using the enzyme-linked immunosorbent assay. The data were submitted to normality, homogeneity of variance, and Mann-Whitney tests (P < .05). RESULTS: Significant differences were found between the irrigating solutions (P < .05) and intracanal medicaments for TGF-ß1 (P < .05). No VEGF release was detected for any group. Our results showed no significant differences among the TAP + 2% CHX and EDTA groups for TGF-ß1 but a significant difference between CH + 2% CHX and the other groups (P < .05). CONCLUSIONS: The use of 2% CHX as the irrigating solution, CH as the intracanal medicament, and 10% EDTA as the final irrigation provides higher TGF-ß1 release from the cervical root dentin, whereas VEGF was not detected. Moreover, TAP and 2% CHX with 10% EDTA as the final irrigation resulted in greater TGF-ß1 release from cervical root dentin than CH + 2% CHX.

Periodontitis and placental growth factor in oral fluids are early pregnancy predictors of gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) affects around 7% to 10% of all pregnancies. Early detection of predisposition to GDM is the first step in developing efficacious preventive treatment. The objective of the present study was to establish the utility of placental proteins presents in oral fluids (gingival crevicular fluid [GCF] and saliva), and periodontal disease status as early pregnancy predictors of GDM. METHODS: A nested case control within a prospective cohort was conducted. Pregnant systemically healthy women, aged between 18 and 40 years at 11 to 14 weeks gestation were included. Samples of oral fluids were collected and a complete maternal/obstetric and periodontal history was obtained. The concentration of placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) were measured by enzyme-linked immunosorbent assay in a nested case control sample of the prospective cohort. Multiple logistic regression models assessed the association. The evaluation of the diagnostic accuracy of the biomarkers was performed through receiver operating characteristic (ROC) curves by calculating the area under the curve (AUC). RESULTS: There were recruited 212 pregnant women at 11 to 14 weeks of pregnancy, of these, 14 women (i.e., 6.6%) developed GDM, and displayed significant greater bleeding on probing (BOP) [P = 0.0003]; periodontal probing depth (PD) [P = 0.0028]; clinical attachment level (AL) [P = 0.0008] and periodontal inflamed surface area (PISA) [P = 0.0001]. Similarly, initial glycemia and GCF-PlGF concentrations were significantly greater in women with GDM [P = 0.0012, and P = 0.0019, respectively]. When data were subjected to ROC curve analysis, the combination of initial glycemia and GCF-PlGF concentration delivered an area under the ROC curve of 0.897. Multiple logistic regression analyses demonstrate an association between glycemia (OR 1.21, 95% confidence interval [CI] 1.06 to 1.38; P = 0.005) and GCF-PlGF concentrations in women who developed GDM (OR 1.68, CI 1.05 to 2.68 P = 0.03). CONCLUSIONS: Within the limitations of the present study, the results support that first trimester maternal glycemia combined with GCF-PlGF concentrations could be a surrogate biomarker for the future development of GDM in pre-symptomatic women.

Growth factors and cox2 in wound healing: an experimental study with ehrlich tumors / Avaliação dos fatores de crescimento e cox-2 na cicatrização de camundongos com neoplasia de ehrlich

ABSTRACT Background: Healing is an innate biological phenomenon, and carcinogenesis acquired, but with common humoral and cellular elements. Carcinogenesis interferes negatively in healing. Aim: To evaluate the histological changes in laparotomy scars of healthy Balb/c mice and with an Ehrlich tumor in its various forms of presentation. Methods: Fifty-four mice were divided into three groups of 18 animals. First group was the control; the second had Ehrlich tumor with ascites; and the third had the subcutaneous form of this tumor. Seven days after tumor inoculation, all 54 mice were submitted to laparotomy. All of the animals in the experiment were operated on again on 7th day after surgery, with resection of the scar and subsequent euthanasia of the animal. The scars were sent for histological assessment using immunohistochemical techniques to evaluate Cox-2 (cyclooxygenase 2), VEGF (vascular endothelial growth factor) and FGF (fibroblast growth factor). Semi-quantitatively analysis was done in the laparotomy scars and in the abdominal walls far away from the site of the operation. Results: Assessing the weight of the animals, the correct inoculation of the tumor and weight gain in the group with tumoral ascites was observed. The histological studies showed that groups with the tumor showed a statistically significant higher presence of Cox-2 compared to the control. In the Cox-2 analysis of the abdominal wall, the ascites group showed the most significant difference. VEGF did not present any significant differences between the three groups, regardless of the site. The FGF showed a significant increase in animals with the tumor. Conclusion: Histological findings in both laparotomy scar and the abdominal wall showed that with Ehrlich's neoplasia there was an exacerbated inflammatory response, translated by more intense expression of Cox-2 and greater fibroblast proliferation, translated by more intense expression of FGF, that is, it stimulated both the immediate inflammatory reactions, observed with Cox-2 reactions, and late scarring by fibroblasts and FGF.

RESUMO Racional: A cicatrização é fenômeno biológico inato, e a carcinogênese adquirido, mas com elementos humorais e celulares comuns. A carcinogênese interfere de forma negativa na cicatrização. Objetivo: Avaliar as modificações histológicas nas cicatrizes laparotômicas de camundongos Balb/c sadios como controles, e com a neoplasia de Ehrlich, em suas diferentes formas de apresentação. Métodos: Foram utilizados 54 camundongos, divididos em três grupos de 18 animais cada um. O primeiro era controle; o segundo com a neoplasia de Ehrlich em sua forma ascítica; e o terceiro na forma subcutânea. Sete dias após a inoculação do tumor, todos os 54 camundongos foram submetidos à laparotomia e reoperados no sétimo dia de pós-operatório, com ressecção da cicatriz e posterior eutanásia. As cicatrizes foram encaminhadas para estudo histológico com técnicas imunoistoquímicas para avaliar Cox-2 (ciclo-oxigenase 2), VEGF (fator de crescimento do endotélio vascular) e FGF (fator de crescimento dos fibroblastos) e analisadas de forma semiquantitativana tanto na cicatriz laparotômica como na parede abdominal mais distante do local operado. Resultados: Avaliando o peso, observou-se a correta inoculação do tumor e o aumento de peso no grupo com a neoplasia na modalidade ascítica. Os estudos histológicos mostraram que os grupos com a neoplasia apresentaram maior presença da Cox-2 em relação ao controle, estatisticamente significante. No estudo da Cox-2 da parede abdominal foi o local em que o grupo ascítico apresentou a diferença mais expressiva. O VEGF não apresentou diferenças significantes entre os três grupos, independentemente do local estudado. O FGF teve aumento significante nos animais com neoplasia. Conclusão: Os achados histológicos encontrados tanto na cicatriz das laparotomias quanto na parede abdominal mostraram que com a neoplasia de Ehrlich houve resposta inflamatória exacerbada, traduzida por expressão mais intensa da Cox-2 e maior proliferação fibroblástica, traduzida por expressão mais intensa do FGF, ou seja, estimulou tanto as reações inflamatórias imediatas, observadas nas reações da Cox-2, como nas cicatriciais tardias com os fibroblastos e o FGF.

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Sunitinib (SU) and pazopanib (PZ) are standards of care for first-line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates into effectiveness on a population-based level is unknown. PATIENTS AND METHODS: We used the International mRCC Database Consortium (IMDC) to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS (OS2) and second-line PFS (PFS2) were also evaluated. RESULTS: We obtained data from 7438 patients with mRCC treated with either first-line SU (n = 6519) or PZ (n = 919) with an overall median follow-up of 40.4 months (95% confidence interval [CI] 39.2-42.1). There were no significant differences in IMDC prognostic groups (p = 0.36). There was no OS difference between SU and PZ (22.3 versus 22.6 months, respectively, p = 0.65). When adjusted for IMDC criteria, the hazard ratio (HR) of death for PZ versus SU was 1.03 (95% CI 0.92-1.17, p = 0.58). There was no PFS difference between SU and PZ (8.4 versus 8.3 months, respectively, p = 0.17). When adjusted for IMDC criteria, the HR for PFS for PZ versus SU was 1.08 (95% CI 0.981-1.19, p = 0.12). There was no difference in RR between SU and PZ (30% versus 28%, respectively, p = 0.15). We also found no difference in any second-line treatment between either post-SU or post-PZ groups for OS2 (13.1 versus 11 months, p = 0.27) and PFS2 (3.7 versus 5.0 months, p = 0.07). CONCLUSIONS: We confirmed in real-world practice that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment.

Molecular mechanism mediating cytotoxic activity of axitinib in sunitinib-resistant human renal cell carcinoma cells.

PURPOSE: This study aimed to clarify the molecular mechanism mediating the cytotoxicity of axitinib, a selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), in sunitinib-resistant renal cell carcinoma (RCC). METHODS: In our previous study (Sakai et al. in BJU Int 112:E211-E220, 2013), a human RCC cell line, ACHN, resistant to sunitinib (ACHN/R), was developed from a parental cell line (ACHN/P). Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared. RESULTS: ACHN/R showed an approximately fivefold higher IC50 of sunitinib than ACHN/P; however, there was no significant difference in the sensitivity to axitinib between these two cell lines. In ACHN/R, despite the lack of a difference in the phosphorylated (p)-Akt or STAT-3 expression between treatment with sunitinib and axitinib, the expression of p-p44/42 mitogen-activated protein kinase (MAPK) and p-VEGFR-2 after treatment with axitinib was markedly down-regulated compared with those after treatment with sunitinib. Furthermore, additional treatment of ACHN/R with an inhibitor of MAPK kinase significantly enhanced the cytotoxic activity of sunitinib, but not that of axitinib. In vivo growth of ACHN/R in nude mice after treatment with axitinib was significantly inhibited compared with that following treatment with sunitinib, accompanying the marked inhibition of angiogenesis. CONCLUSIONS: Antitumor activity of axitinib in RCC cells even after the acquisition of resistance to sunitinib could be explained, at least in part, by the inactivation of p44/42 MAPK and VEGFR-2, which were persistently phosphorylated in sunitinib-resistant RCC cells under treatment with sunitinib.

Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate.

CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.

Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF treatment

BACKGROUND: Angiogenesis is an early stage of psoriatic lesion development, but less is known about lymphagiogenesis and its role in the development of psoriasis. OBJECTIVE: To examine the expression of specific lymphatic markers and lymphatic growth factors in untreated psoriatic skin, in the unaffected skin of patients and skin of healthy volunteers, as well as their alteration after treatment with an anti-TNF agent. METHODS: Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after treatment with etanercept, as well as in the skin biopsies of 10 healthy volunteers. RESULTS: The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent statistically significant increases in untreated psoriatic skin compared with non-lesional skin, in contrast to LYVE-1, which did not involve significant increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on fibroblasts presented with higher expression in lesional skin than in non-lesional adjacent skin. CONCLUSION: Remodeling of lymphatic vessels possibly occurs during psoriatic lesion development, parallel to blood vessel formation. The exact role of this alteration is not yet clear and more studies are necessary to confirm these results. .

Cambios moleculares en los márgenes de resección en el carcinoma de células escamosas de cavidad oral / Molecular changes in the resections borders in squamous cell cancer of oral cavity

Evaluación molecular de márgenes de resección en pacientes con carcinoma de células escamosas de cavidad oral sometidos a cirugía. 16 pacientes con carcinoma escamoso de cavidad oral, en cualquiera de sus localizaciones, sin tratamientos previos, intervenidos quirúrgicamente en el 2011. La pieza operatoria fue procesada por anatomía patológica a través del método tradicional, realizándose cortes adicionales que incluían: tumor y 0,5 cm de margen no tumoral. Se realizó hematoxilina-eosina y complementó con inmunomarcaje para p53, PCNA, Ki-67, factor de crecimiento epidérmico y receptor de crecimiento endotelial vascular. De los 16 pacientes en estudio la mayoría eran del género masculino, la edad promedio fue cercana a los 60 años, la mayoría eran pacientes consumidores de tabaco y alcohol. La lengua fue la localización más frecuente y los tumores se encontraban en un estadio avanzado (estadio III y IV). Estudio molecular: todos los marcadores evaluados se encontraban positivos en los márgenes de resección en el 93,75% de los pacientes. Los marcadores de proliferación celular como el PCNA y Ki-67 así como el p-53 se encontraban positivos entre 1,5 cm a 2 cm del tumor con un marcaje intenso. Por el contrario, el factor de crecimiento epidérmico el receptor de crecimiento endotelial vascular se encontraban positivos hasta 1,5 cm pero con menor intensidad. En el cáncer oral podemos observar con frecuencia cambios moleculares en el tejido aparentemente sano que rodea el tumor hasta por lo menos 15 mm.

The molecular evaluation of resection margins in patients with squamous cell carcinoma of oral cavity who underwent surgery. Field of cancerization concept. We included 16 patients with oral cavity squamous cell carcinoma in any of their locations,without pre treatment, surgically treated in our hospital in the 2011 year. The surgical specimen was processed by the pathology department of our institution, through the traditional method, additional sectioned including the tumor and at least 0.5 cm margin non tumorigenic. Study was performed hematoxylin eosin and was supplemented with immunostaining for p53, PCNA, Ki-67, epidermal growth factor receptor and vascular endothelial growth factor receptor. The most important features of the 16 patients studied were: The majorities were male, the average age was around 60 years old; most of them were tobacco and alcohol consumers. The tongue was the most frequent location and most of the tumors were in an advanced stage (stage III y IV). In molecular evaluation all the markers were positive in the resection margins in 93.75% of all patients. The cell proliferation markers suchas PCNA and Ki-67 and the p-53 were positive 1.5 cm to2 cm tumor with intense staining. Conversely, epidermal receptor grow factors and vascular endothelial grow factor receptor were positive up to 1.5 cm but with less intensity. In oral cancer can often observe molecular changes in the apparently healthy tissue surrounding the tumor to at least 15 mm.

Testing intravitreal toxicity of rapamycin in rabbit eyes / Toxicidade intravítrea da rapamicina em olhos de coelhos

PURPOSE: To evaluate retinal toxicity of varying doses of rapamycin when injected intravitreally in rabbits. Rapamycin is a potent immunosuppressive agent with significant antitumor and antiangiogenic properties, clinically approved for prevention of organ transplant rejection. METHODS: Twelve New Zealand albino rabbits were divided into four groups. Four different doses of rapamycin were prepared in 0.1 ml: 20 µg, 50 µg, 200 µg, and 1000 µg. Each concentration was injected in one eye of three rabbits, and 0.1 ml volume of sterile BSS was injected into the contralateral eye of the three rabbits. Slit-lamp and fundoscopic examinations were performed and the animals were observed for 2 weeks for signs of infection, inflammation, and toxicity. A baseline ERG was performed before drug treatment and at day 14, after which the rabbits were euthanized. Histology of the enucleated eyes was studied to look for retinal toxicity. RESULTS: ERG results showed some decrease in scotopic response; however this was not dose related. ERG results were normal at 20 µg. Histological results showed no retinal toxicity in all groups. CONCLUSION: Although ERG changes were identified at dosages between 50-1000 µg, the histology of all groups up to 1000 µg did not show any discernable abnormalities.

OBJETIVO: Avaliar a toxicidade da injeção intravítrea de diferentes doses de rapamicina para a retina de coelhos. Rapamicina é uma potente droga imunossupressora aprovada clinicamente para a prevenção da rejeição de transplantes de orgãos. MÉTODOS: Doze coelhos albinos da Nova Zelândia foram usados neste estudo. Foram divididos em quatro grupos. Quatro diferentes doses de rapamicina foram preparadas nas seguintes concentrações: 20 µg, 50 µg, 200 µg, 1000 µg. Foram realizadas injeções intravítreas de 0,1 ml de cada concentração em um olho de três coelhos e 0,1 ml de solução salina foi injetada no olho contralateral de cada coelho. Foram realizadas biomicroscopia e fundoscopia e observamos sinais de inflamação, infecção ou toxicidade durante duas semanas. Fizemos um ERG antes do tratamento e outro 14 dias depois da injeção intravítrea. Os animais foram sacrificados, fizemos a enucleação dos olhos e preparamos o tecido para a avaliação histológica. RESULTADOS: Os resultados do ERG e da histologia demonstraram diminuição da resposta escotópica, entretanto essa diminuiçãão foi dose dependente. A histologia foi normal em todos os grupos. CONCLUSÃO: A injeção intravítrea de rapamicina levou a alterações eletrorretinográficas nos grupos de 50-1000 µg, entretanto a histologia foi normal em todos os grupos até 1000 µg.