Immunotherapy for EGFR-mutant non-small cell lung cancer after EGFR-TKI acquired resistance / 国际肿瘤学杂志

Epidermal growth factor receptor (EGFR) -mutant advanced non-small cell lung cancer (NSCLC) was previously regarded as a cold tumor according to tumor immune microenvironment (TIME) . However, recent studies have found that EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment can transform the host immunity from immunosuppressive to immunosupportive state, bringing new hope for immunotherapy. There are four main therapeutic strategies for patients after EGFR-TKIs acquired resistance: immunotherapy alone (Im) , immunotherapy plus chemotherapy (Im+C) , immunotherapy plus antiangiogenic drugs (Im+A) , and immunotherapy combined with antiangiogenic drugs and chemotherapy (Im+A+C) . Among them, the efficacy of Im is extremely limited, being significantly lower than that of chemotherapy alone, while there is still scarce evidence for the efficacy of Im+A with few clinical studies. The combination of Im+C and Im+A+C shows better efficacy than chemotherapy alone. Im+A+C has a superior clinical outcome to Im+C. Additionally, the EGFR L858R mutation subgroup benefits more from Im+C than the EGFR 19 del mutation subgroup. The T790M-negative subgroup has a greater benefit from Im+A+C than the T790M-positive subgroup. In general, the strategy of combining immunotherapy with chemotherapy and/or an antiangiogenic drug represents a novel and promising method for treating EGFR-mutant NSCLC after EGFR-TKI failure.

Role of immunotherapy in metastatic EGFRm NSCLC: Is it relevant?

EGFR?TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild?type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR?TKI?targeted therapy. The ICIs targeting the programmed cell death?1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD?L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD?L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm?TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR?TKIs are being evaluated in TKI?failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population

Streptozotocin-induced diabetic retinopathy in mice: Model establishment and evaluation / 第二军医大学学报

Objective: To establish streptozotocin (STZ)-induced diabetic retinopathy model in mice, and to observe the pathological changes of the retina in early diabetic stages and the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 in the mouse model. Methods: C57BL/6J mice, aged 6-8 weeks, received intraperitoneal injection of STZ (55 mg/kg) once a day for 5 d. The fasting blood glucose concentration was measured 1 week after injection. The diabetic and control mice were fed for 5 months. Then the morphological changes of retina in diabetic mice were analyzed by H-E staining, Evans blue perfusion angiography and retinal vascular network digestion. The expression of VEGF and its receptors VEGFR1, VEGFR2 in diabetic retinopathy was analyzed by quantitative real-time PCR and Western blotting. Results: Compared with the control group, the blood glucose levels of the model group were significanlty increased 1 week, 1 to 5 months after injection (all higher than 16.5 mmol/L, all P<0.01). At 5 months after injection, the whole retina of the model group became thinner; the number of photoreceptor cells, inner and outer nuclear cells were decreased and disorderly arranged; the blood vessels went tortuously with leakage and leakage spots; the number of vascular endothelial cells was increased, with altered morphology; the number of peripheral cells was decreased; and there were no cellular capillaries and lumen occlusion. The expression levels of VEGF, VEGFR1 and VEGFR2 protein and mRNA were significantly increased in the model group compared with the control group (all P < 0.01). Conclusion: Diabetic retinopathy mouse model has been successfully constructed, with proliferative diabetic retinopathy appearing 5 months after diabetes, and the expression levels of VEGF, VEGFR1 and VEGFR2 are increased in the retina of diabetic mice.

Fatores de risco associados à intervenção com injeção intravítrea de anti-VEGF em pacientes com edema macular diabético / Risk factors related to the intervention with intravitreal anti-VEGF injection in patients with diabetic macular edema

Resumo Objetivo: Propor um modelo de regressão logística para auxiliar na decisão de realização da injeção intravítrea (IIV) de anti-VEGF, a partir da quantificação e hierarquização dos fatores de risco que compõem o perfil dos indivíduos diabéticos. Métodos: Trata-se de estudo transversal, observacional e inferencial, realizado em três instituições da Paraíba, de julho de 2015 a setembro de 2016. O modelo de regressão logística foi utilizado para obtenção do modelo preditivo e os dados foram analisados no software R®. Resultados: Foram avaliados 80 pacientes com diabetes tipo 1 ou 2, maiores de 18 anos, dos quais 57,5% não tiveram indicação de IIV e 42,5% receberam indicação deste tratamento. No grupo com edema macular diabético (EMD), a média de idade foi de 60,65 anos, sendo 52,94% do sexo feminino. Ainda nesse grupo, a maioria apresentou retinopatia diabética não-proliferativa severa ou retinopatia proliferativa (79,41%). Foram identificados como fatores de risco para EMD: o indivíduo ser aposentado (OR=5,22; p-valor 0,05), ter histórico pessoal de retinopatia diabética (OR=20,27; p-valor 0,006) e de tratamento prévio com anti-VEGF (OR=23,23; p-valor 0,002). Conclusão: Os resultados da pesquisa evidenciaram que um indivíduo diabético com baixa visual e apresentando esses três fatores deve ser encaminhado o quanto antes ao especialista, pois possui, com 91,17% de acerto, risco de apresentar EMD com necessidade de IIV de anti-VEGF. Essa ferramenta pode servir como coadjuvante na tomada de decisão, sobretudo do não-retinólogo, a fim de encaminhar para diagnóstico e tratamento precoces os indivíduos com EMD, o que pode ser decisivo na prevenção da perda visual irreversível nesses pacientes.

Abstract Purpose: To propose a predictive model to aid in the decision to perform the intravitreal anti-VEGF injection, based on the risk factors quantification and hierarchy presented by diabetic patients. Methods: It is a cross-sectional, observational and inferential study carried out in three institutions in Paraíba from July 2015 to September 2016. The logistic regression model was used to obtain the predictive model and data were analyzed in R(r) software. Results: Eighty patients with type 1 or 2 diabetes, over 18 years of age, were included, 57.5% of whom had no indication of IIV and 42.5% received an indication of this treatment. In the group with diabetic macular edema (DME), the mean age was 60.65 years, of which 52.94% were female. In this group, the majority presented severe non-proliferative diabetic retinopathy or proliferative retinopathy (79.41%). The main risk factors for DME were: be retired (OR = 5.22, p-value0.05), had a personal history of diabetic retinopathy (OR = 20.27, p-value 0.006), and previous treatment with anti-VEGF (OR = 23.23, p-value 0.002). Conclusion: The results of the research showed that a diabetic patient with low visual acuity and presenting these three factors should be referred as soon as possible to the specialist, since he presents a risk of presenting DME with need for anti-VEGF IIV, with 91.17% of accuracy. This tool can serve as an adjunct to decision making, especially the nonretinologist, in order to refer individuals with EMD to early diagnosis and treatment, which may be crucial in preventing irreversible visual loss in these patients.

Effects of Acupuncture-rehabilitation Therapy on Neurological Function and Expression of Vascular Endothelial Growth Factor Receptors, Flt-1 and Flk-1, after Focal Cerebral Ischemia in Rats / 中国康复理论与实践

Objective To explore the effect of acupuncture-rehabilitation therapy on neurological function and expression of Flt-1 and Flk-1, members of vascular endothelial growth factor receptors, after permanent focal cerebral ischemia in rats. Methods Ninety male Sprague-Dawley rats were divided into five groups, namely sham group, model group, acupuncture group, rehabilitation group and acupunc-ture-rehabilitation group, and each group was further divided into 3-day, 7-day and 14-day subgroups, equally. Their middle cerebral arteries were occluded except those of sham group. The sham and model groups accepted no treatment, while the acupuncture group accepted clus-ter needling of scalp acupuncture, the rehabilitation group accepted treadmill training, and the acupuncture-rehabilitation group accepted both acupuncture and treadmill training. They were assessed with modified Neurologic Severity Score (mNSS) 3, 7 and 14 days after model-ing, while the expression of Flt-1 and Flk-1 were determined with Western blotting. Results The mNSS score reduced in all the treatment groups (P<0.05) compared with that of the model group at every time point, and was the least in the acupuncture-rehabilitation group (P<0.05) 7 and 14 days after modeling among the treatment groups. Meanwhile, the expression of Flt-1 and Flk-1 protein increased in all the treatment groups (P<0.05), and was the most in the acupuncture-rehabilitation group (P<0.05). Conclusion Acupuncture-rehabilitation thera-py can promote the neurological function recovery in rat with permanent focal cerebral ischemia, which may be associated with the continu-ous inducement of Flt-1, Flk-1 protein expression in ischemic penumbra cortex.

Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis

The shaping of new blood vessels is a significant event in cancer growth and metastasis. Therefore, the molecular system of cancer angiogenesis has garnered considerable interest in cancer research. The vascular endothelial growth factor (VEGF) and VEGF receptor pathway are recognized as the key regulators of the angiogenic process. Activation of the VEGF/VEGF-receptor pathway initiates signaling cascades that promote endothelial cell growth, migration, and differentiation. Recently, VEGF was shown to play a role in the recruitment of bone marrow-derived endothelial progenitor cells to neovascularization sites. The role of VEGF in promoting tumor angiogenesis and the occurrence of human cancers has led to the rational design and development of agents that selectively target this pathway. Moreover, these anti-VEGF/VEGF receptor agents show therapeutic potential by inhibition of angiogenesis and tumor growth in preclinical models. In this review, we summarize the role of the VEGF pathway during tumor angiogenesis.

Influence of vascular endothelial growth factor inhibition on simple renal cysts in patients receiving bevacizumab-based chemotherapy

PURPOSE: Although angiogenesis has been implicated in the promotion of renal cyst growth in autosomal dominant polycystic kidney disease, no studies have investigated the role of angiogenesis in the growth of simple renal cysts. The aim of current study was to investigate the effect of chemotherapy with the antivascular endothelial growth factor antibody bevacizumab on renal cyst development and growth in cancer patients. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 136 patients with a variety of cancers that were treated with bevacizumab-based chemotherapy for metastatic disease. The presence of and changes in renal cysts were evaluated by retrospective analysis of computed tomography scans performed for assessment of tumor response to bevacizumab-based therapy. RESULTS: The median age of the patients was 64 years. Renal cysts were identified in 66 patients, in whom 33 (50%) had a single cyst and the rest had 2 or more cysts. The average dose of bevacizumab was 2.68 mg/kg per week. Median duration of treatment was 33 weeks. Average cyst size was 1.9±2.4 cm at the beginning of the study and the majority of the cysts (54 patients, 84%) did not change in size or shape during bevacizumab treatment. No patients were identified with new cysts. Cyst size changed in 10 patients (16%): an increase of 15% to 40% from the baseline size in 5 patients and a decrease in size of 10% to 70% in another 5 patients. The duration of bevacizumab therapy was significantly longer in the subgroup of patients with diminished or increased cyst size than in the patients with stable cyst size: 62 weeks versus 29 weeks, respectively (p=0.0002). CONCLUSIONS: Our data demonstrated that simple renal cysts were stable in size and number in the vast majority of cancer patients treated with bevacizumab.

Regulation of Giα Protein Expression by Vasoactive Peptides in Hypertension: Molecular Mechanisms.

Guanine nucleotide regulatory proteins (G proteins) play a key role in the regulation of various signal transduction systems, including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol (PI) turnover, which are implicated in the modulation of a variety of physiological functions, such as platelet functions, including platelet aggregation, secretion, and clot formation and cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have been shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G proteins (Giα) and mRNA have been reported in different models of hypertension, whereas Gsα levels are shown to be unaltered. The enhanced levels of Giα proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The levels of vasoactive peptides including ET-1 and Ang II and growth factors are augmented in hypertension and contribute to the enhanced expression of Giα proteins in hypertension. In addition, oxidative stress due to enhanced levels of Ang II and ET-1 is enhanced in hypertension and may also be responsible for the enhanced expression of Giα proteins observed in hypertension. Furthermore, Ang II- and ET-1-induced transactivation of growth factor receptor through the activation of MAP kinase signaling is also shown to contribute to the augmented levels of Giα in hypertension. Thus, it appears that the enhanced levels of vasoactive peptides by increasing oxidative stress and transactivation growth factor receptors enhance MAP kinase activity that contribute to the enhanced expression of Giα proteins responsible for the pathogenesis of hypertension. In this review, we describe the role of vasoactive peptides and the signaling mechanisms responsible for the enhanced expression of Giα proteins in hypertension.

FGF-23: estado da arte / FGF-23: state of the art

Há aproximadamente 10 anos descobriuse um hormônio denominado FGF-23 (fator de crescimento de fibroblastos 23), um membro da família dos fatores de crescimento de fibroblastos, cujas funções atualmente conhecidas envolvem o metabolismo do fósforo (P) e a inibição da 1α hidroxilase, enzima responsável pela síntese de calcitriol. Tal descoberta possibilitou um novo entendimento sobre os mecanismos de controle do P, um elemento associado com mortalidade, especialmente na doença renal crônica (DRC). Nesta revisão descreveremos diversos aspectos deste hormônio, desde a sua descoberta, função, produção, mecanismo de ação, até os últimos estudos clínicos envolvendo o mesmo. Posteriormente, abordaremos as possíveis repercussões destes estudos na prática clínica.

Approximately 10 years ago, a member of the family of the fibroblast growth factors, the hormone FGF-23 (fibroblast growth factor 23) was discovered. Its currently known functions involve phosphorus (P) metabolism and inhibition of 1αhydroxylase, the enzyme responsible for the synthesis of calcitriol. That discovery led to a better understanding of the mechanisms of P control, an element associated with mortality, especially in chronic kidney disease. This study reviews several aspects of that hormone, such as its discovery, function, production, mechanism of action, and the most recent clinical studies about it. Afterwards, a discussion about the possible effects of those studies on clinical practice will be presented.

TLR4 signaling promotes secretion of VEGF/IL-8 in prostate cancer PC3 cells and related mechanism / 第二军医大学学报

Objective: To study TLR4 expression in human prostate cancer PC3 cells and the related intracellular signaling mechanisms. Methods: Human prostate cancer PC3 cells were stimulated with TLR4-specific ligand lipopolysaccharide (LPS), then the cells and supernatants were collected 0, 2, 6, 12, 24, and 48 hours after LPS stimulation. TLR4 mRNA and protein expression was examined by reverse transcription-PCR and Western blotting analysis, respectively. The mRNA expression of TGF-β, VEGF, 1L-8, COX-2, and MMP3 was also measured by reverse transcription-PCR, and the levels of VEGF, IL-8 in the supernatants were examined by ELISA. To further study the related signaling pathway, MAPK and NF-κB signaling pathways were blocked by specific inhibitors in PC3 cells before LPS stimulations the cells were collected after 4 hours and the supernatants were collected after 24 hours; and the above mentioned factors were examined by reverse transcription-PCR and ELISA again. Results: TLR4 expression was up-regulated by LPS stimulation in human prostate cancer PC3 cells, which significantly increased mRNA expression of TGF-β, VEGF, IL-8, COX-2, and MMP3 and secretion of VEGF and IL-8 in the supernatants (P<0.05); further study showed that p38 MAPK and NF-κB signal pathways were involved in the process. Conclusion: TLR4 signaling promotes VEGF and IL-8 secretion through p38 MAPK and NF-κB signal pathways.

Insulin promotes rhesus retinal vascular endothelial cells angiogenesis via VEGF-A/VEGFR2 pathway / 中华内分泌代谢杂志

Rhesus retinal vascular endothelial cell line RF/6A cells were treated with human insulin. Cell proliferation, migration, and lumen formation, as well as the expressions of vascular endothelial growth factor-A ( VEGF-A ), VEGF-A receptors, and phosphorylated receptors were measured. Insulin promoted RF/6A cell proliferation, migration, and lumen formation ( all P＜0. 01 ). Insulin increased the expression of VEGF-A mRNA and improved its protein activity ( all P＜0. 05 ), and promoted the expression of VEGFR2 mRNA and its phosphorylation ( both P＜0. 01 ). There was no significant difference in the expression of VEGFR1 mRNA among the groups ( P＞0. 05 ).

Expression of extracellular signal-regulated kinase in lesions of psoriasis vulgaris / 中华皮肤科杂志

Objective To investigate the expression and activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), its upstream molecule, epidermal growth factor receptor (EGFR), and downstream transcription factor, Ets-like protein 1 (ELK-1), in lesions of psoriasis vulgaris, and to evaluate the relationship between ERK pathway and psoriasis vulgaris. Methods Tissue samples were obtained from the lesions of 40 patients with psoriasis vulgaris and normal skin of 20 normal human controls. Immunohistochemistry and Western blot were performed to detect the expressions of phosphorylated ERK1/2, EGFR and ELK-1 in the tissue samples.Results As immunohistochemistry showed, the integrated optical density (IOD) of p-ERK1/2, p-EGFR and p-ELK-1 was 269.85 ± 57.96, 136.88 ± 30.33 and 237.61 ± 56.29 respectively in the psoriatic lesions, significantly higher than that in the normal controls ( 140.24 ± 24.42, 110.66 ± 28.99 and 119.04 ± 21.99, respectively, all P ＜ 0.05). A positive correlation was observed between the expression of p-EGFR and p-ERK1/2(r = 0.57, P ＜ 0.05) and between that of p-ERK1/2 and p-ELK-1 (r=0.72,P＜0.05) in psoriatic lesions.Conclusion The enhanced signal transduction through phosphorylated EGFR→ERK1/2→ELK-1 pathway may play a certain role in the pathophysiological process of psoriasis vulgaris.

Changes of fibroblast growth factor-21 and its receptors in high-fat diet fed apoE~(-/-) mice / 中华内分泌代谢杂志

Objective To investigate the effects of high-fat diet induced insulin resistance on fibroblast growth factor-21 (FGF-21) and its receptors expression in ApoE~(-/-) mice. Method Male ApoE~(-/-) mice were randomly divided into normal-chow group(NF,n=20)and high-fat fed group(HF,n=20) and fed for 16 weeks. The insulin sensitivity and glucose-lipid metabolism in awake mice were evaluated by hyperinsulinemic-euglycemic clamp technique combined with 3-[~3H]-glucose as a tracer. The Mrna expressions of FGF-21,β-klotho, and FGFR1-4 were measured by quantitative real-time PCR. FGF-21 protein levels were determined by Western blot. Results Fasting blood glucose, plasma insulin and free fatty acids, triglycerides, free fatty acids, and cholesterols were significantly elevated in HF group compared with NF group(all P<0.01). During the steady-state of clamp, plasma insulin was significantly higher in HF group than that in NF group(P<0.01), and glucose infusion rate was also significantly decreased(P<0.01). At the end of insulin clamp, glucose disappearance rate was significantly lower in HF group than that in NF groups(P<0.01). Hepatic glucose production in NF group was suppressed by 70% ,while in HF group it was suppressed by 51%. The FGF-21 Mrna expressions of hepatic and adipose tissues in HF group were significantly increased compared with NF group(both P<0.01), and β-klotho Mrna expressions increased(P<0. 05). In hepatic and adipose tissues, FGFRI, Mrna expressions were higher in HF group than those in NF group(both P<0.01) ,and FGFR3 Mrna increased(P<0.01 and P<0.05, respectively). In hepatic tissue,FGFR4 Mrna levels were significantly up-regulated in HF group(P<0. 05). Plasma FGF-21 levels were elevated in HF group compared with NF group(P<0.01) ,and FGF-21 protein expressions of hepatic and adipose tissues were also increased(both P<0.05). Conclusion FGF-21, β-klotho, FGFR1, and FGFR3 were significantly up-regulated in ApoE~(-/-) mice fed by high-fat diet, and they might be the targets in regulating glucose-lipid metabolism by FGF-21.

Expression of nerve growth factor receptors p75 in human bladder carcinoma and its influence by hypoxia / 中华泌尿外科杂志

Objective To explore the expression of the nerve growth factor receptors p75 (p75NGFR) in human bladder carcinoma samples, and the effects of hypoxia on the expression of p75NGFR in human bladder cancer ceils. Methods The expression of p75NGFR in 107 bladder cancer and lymph node specimens were immunohistochemically investigated. The expression of p75NGFR in bladder cancer cell line (T24) was assessed by immunocytochemistry, and reverse tran-scription-PCR in the Normoxic Condition (air, 5%CO2) and in hypoxia condition(10%O2, 5%CO2, 85%N2). Results p75NGFR expressed in 46 of 107(43.0%) tumor samples. There was no signifi-cant correlation between p75NGFR and the factors such as gender, age, extent of the tumors, and pathologic grading(P0.05), p75NGFR was expressed in examined cell line T24, and also expressed in 5 of 24 bladder tumors in metastasized lymph node specimens. Hypoxia markedly down-regulated the expression of p75NGFR of T24 cell line at third day. Conclusions It is suggested that p75NGFR is expressed less in lymph node metastasis. Hypoxia markedly inhibited expression of p75NGFR of T24 cell lines.

Roles of basic fibroblast growth factor in the seft-renewal of human embryonic stem cells / 国际生物医学工程杂志

The self-renewal and multi-lineage developmental potential are the unique properties of human embryonic stem(ES) cells. The growth factors that maintain human or mouse embryonic stem cells are different. Leuckemia inhibitory factor(LIF) does not maintain self-renewal of human ES cells(hESCs). Recently, a few growth factors have been found to be biologically relevant for hESCs functions in vitro, among them the basic fibroblast growth factor(bFGF) is one of the most significant regulators of hESCs self-renewal. The purpose of this review is to introduce the recent progress in the research on the expressions of bFGF and its receptors and their functions in hESCs.

Expressão protéica no endométrio durante a fase lútea do ciclo menstrual / Endometrial protein expression during the luteal phase of the menstrual cycle

Introdução: O objetivo foi avaliar a expressão de algumas proteínas no endométrio durante a fase lútea do ciclo menstrual de mulheres férteis e inférteis, por meio imunoistoquímica de micro-arranjos teciduais (TMA). Métodos: Analisou-se a expressão de dez proteínas em 52 amostras de endométrio obtidas nas fases lútea inicial, intermediária (janela de implantação) e final. Resultados: As proteínas, fator inibidor de leucemia (LIF), fator de crescimento insulinóide tipo 1 (IGF-1), receptor de progesterona (PR), claudina-4, receptor de fator de crescimento vascular endotelial 3 (VEGFR-3) e citoqueratina 7 (CK-7) mostraram-se expressas no endométrio nas fases lútea inicial, intermediária e final. A proteína morfogenética óssea 4 (BMP-4) expressou-se no endométrio nas fases lútea inicial e intermediária. As proteínas citoqueratina 17 (CK-17), substância solúvel 100 (S100) e calretinina não se expressaram no endométrio durante os três períodos avaliados. Houve correlação entre as expressões protéicas de LIF, IGF-1 e PR. As proteínas LIF e BMP-4 foram diferencialmente expressos no endométrio nas fases lútea inicial, intermediária e final. As proteínas claudina-4 e PR não se expressam simultâneamente no endométrio durante a fase lútea. Conclusão: Baseados nos resultados deste estudo podemos sugerir que a presença das proteínas LIF, IGF-1 e PR durante a janela implantacional teria relevância como preditor do adequado desenvolvimento do endométrio.

Introduction: The objective of this study was to evaluate endometrial protein expressions from fertile and infertile women during the luteal phase of the menstrual cycle by immunohistochemistry in tissue microarrays (TMA). Method: The expression of ten proteins obtained from 52 endometrial samples in the initial, mid (window of implantation) and late (premenstrual) phases of the menstrual cycle were evaluated. Results: The proteins leukemia inhibitory factor (LIF), insulin like growth factor 1 (IGF-1), progesterone receptor (PR), claudin-4, vascular endothelial growth factor receptor 3 (VEGFR-3), and cytokeratin 7 (CK-7) were expressed in the endometrium in the three intervals of the luteal phase. Endometrial expression of the morphogenetic bone protein 4 (BMP-4) occurred during the initial and mid luteal phases. Cytokeratin 17, substance 100 and calretinin were not expressed in the luteal phase. There were positive correlations among endometrial expressions of LIF, IGF- 1, and PR. LIF and BMP-4 were differently expressed in the initial, mid and late phases of the luteal phase. Claudin-4 and PR did not express simultaneously during the different intervals of the luteal phase. Conclusion: These findings suggest that positively correlated endometrial expressions of LIF, IGF-1 and PR at the window of implantation could characterize an adequately developed and receptive endometrium.

Expression of vascular endothelial growth factor and its receptors in the distracted periosteum after mandibular distraction osteogenesis

Significance of bFGF,FGFR-2 and Hpa expression in gastric precancerous lesions and gastric carcinoma tissues / 中国实用内科杂志

Objective To study the expression of basic fibroblast growth factor(bFGF),fibroblast growth factor receptor-2(FGFR-2)and heparanase(Hpa)in the tissues of gastric cancer and precancerous lesions,and to explore its significance in the carcinogenesis and malignant progression of stomach.Methods The expression of bFGF,FGFR-2 and Hpa were detected by immunohistochemistry in 145 cases of paraffin-embedded specimens from different gastric mucosa,including 30 cases of chronic superficial gastritis(CSG),29 of intestinal metaplasia(IM),31 of dysplasia(Dys)and 55 of gastric carcinoma(GC).Results The expression of bFGF and FGFR-2 in CSG group was significantly lower than that of the other three groups(P

Moleculobiological Analysis of Fibroblast Growth Factor Receptors in Korean Patients with Craniosynostosis

Fibroblast growth factor(FGF) play a critical role in bone growth and development, affecting both chondrogenesis and osteogenesis. The authors believe, many craniosynostosis disorders to be linked with activating mutations in the fibroblast growth factor receptors (FGFRs). In recent studies, detected mutations of the FGFR gene has been reported in some syndromic craniosynostosis patients. So far sequence analysis of FGFR in syndromic craniosynostosis has been reported in many Caucasian patients. But Asian patients, especially in Koreans, only several cases were reported. The authors performed a prospective study, evaluating molecular diagnosis of FGFR 1, 2 and 3 in six Korean patients with craniosynostosis(four with isolated craniosynostosis and two with craniosynostosis syndrome) and four normal child as a control group, by polymerase chain reaction(PCR) followed by direct sequencing methods. The results did not demonstrate, any mutation in normal child but mutations in all six patients with craniosynostosis were seen. Three of four patients with isolated craniosynostosis carried mutation in exon 5 of FGFR 1 and exon 10 of FGFR 3 and two patients with craniofacial synostosis syndrome in exon 7, 10 of FGFR 3. Mutation for the same amino acid residue on FGFRs was not found. But two patients with isolated craniosynostosis and one patient with craniofacial synostosis syndrome had the same mutation pattern in exon 10 of FGFR 3 (Met363Val). Then more investigative attempts are needed to correlate a craniosynostosis and mutation in FGFRs with a large sample of patients.

Significance of transforming growth factor receptors expressing in oxazolone-induced colitis model in mice / 中华消化杂志

Objective To observe the expression of TGF?RⅠ,TGF?RⅡ and Smad7 in oxazolone-induced colitis of mice and to investigate the role of the TGF? signal transduction on pathogenesis of colitis. Methods Balb/c mice were pre-sensitized by skin painting with 0.2 ml 3% oxazolone on day 0 and 1 followed by intrarectal administration of 0.15 ml 1% oxazolone on day 7. The mice were sacrificed after 3 days. Colitis was evaluated by macroscopic and microscopic examination. The expressions of TGF?RⅠ, TGF?RⅡ and Smad 7 were examined by immunohistochemical study and Western blot respectively. All the results were compared with the controls. Results Twenty-four hours after intrarectal administration of oxazolone, the mice presented anorexia, less moving, loose stool, hematochezia or occult blood(+) and weight loss. The macroscopic and microscopic scores in two groups were 0.17?0.41, 2.67?1.03 and 2.33?0.52, 8.17?0.75, respectively. In the normal intestine, TGF?RⅠ, TGF?Ⅱ and Smad7 were mainly co-localized on the upper part of the villus. However, their expression was not only throughout the villus including fundus of crypts, but also in the mononuclear cells of the lamina propria and submucosa in the experimental intestine. The amounts of TGF?RⅠ, TGF?Ⅱ, Smad7 and the ratio of TGF?RⅠ/Ⅱ in control and colitis groups were 3.40?1.25, 21.71?6.97, 8.95?2.12, 0.16?0.01 and 6.49?3.18, 4.40?3.34, 17.92?6.80, 2.14?1.61, respectively. Conclusions Decreased TGF?RⅡ and increased Smad7 expressions indicate the abnormality of TGF? signal transduction in oxazolone-induced colitis. These pathologic and immunologic characteristics may resemble human ulcerative colitis.