Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis

Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p < 0.01). Lymphatics in metastatic tumors arose from small lymphatics, and displayed distinct molecular and morphological profiles compared with those found in normal lymphatics. Smaller lymphatic subtypes were more abundant in skin (2.5-fold, p < 0.01) than in body wall, providing a richer source of lymphatics for VEGF-D⁺ skin tumors, a phenomenon also confirmed in human samples. This study shows that the proximity of a VEGF-D⁺ primary tumor to small lymphatics is an important determinant of metastasis. These observations may explain why tumor location relative to the lymphatic network is prognostically important for some human cancers.     

Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis

Metastasis to regional lymph nodes is an important and early event in many tumors. Vascular endothelial growth factor-C (VEGF-C), VEGF-D and their receptor VEGFR-3, play a role in tumor spread via the lymphatics, although the timing of their involvement is not understood. In contrast, VEGFR-2, activated by VEGF-A, VEGF-C and VEGF-D, is a mediator of angiogenesis and drives primary tumor growth. We demonstrate the critical role for VEGFR-3, but not VEGFR-2, in the early events of metastasis. In a tumor model exhibiting both VEGF-D-dependent angiogenesis and lymphangiogenesis, an antibody to VEGFR-2 (DC101) was capable of inhibiting angiogenesis (79 % reduction in PECAM + blood vessels) and growth (93 % reduction in tumor volume). However, unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). Early excision of the primary tumors demonstrated that VEGF-D-mediated tumor spread precedes angiogenesis-induced growth. Small but highly metastatic primary human breast cancers had significantly higher lymphatic vessel density (23.1 vessels/mm²) than size-matched (11.7) or larger non-metastatic tumors (12.4) thus supporting the importance of lymphatic vessels, as opposed to angiogenesis-mediated primary tumor growth, for nodal metastasis. These results suggest that lymphangiogenesis via VEGF-D is more critical than angiogenesis for nodal metastasis.     

原发性高血压病患者血管紧张素转换酶的基因多态性分析

目的：采用三条引物法进行血管紧张素转换酶(ACE)基因分型,并与Rigat法进行比较,探讨ACE基因多态性与原发性高血压病(EH)之间的关系。方法：抽取外周血DNA,分别用三条引物法和Rigat法对128例EH患者进行ACE基因分型,并以150例正常人作对照组。结果：Rigat法对DD型的错判率为22．22％。正常血压人群ACE基因DD型、Ⅱ型、ID型分别有10、62、78例,占6．67％、41．33％、52％,Ⅰ和D的等位基因频率是67％、33％;原发性高血压病人群ACE基因DD型、Ⅱ型、ID型分别有14、47、67例,占10．94％、36．72％、52．34％,Ⅰ和D的等位基因频率是63％、37％。结论：ACE基因多态性与原发性高血压有一定关系。     

Dental age assessment of young Iranian adults using third molars: A multivariate regression study

BackgroundIn recent years, a noticeable increase in forensic age estimations of living individuals has been observed. Radiologic assessment of the mineralisation stage of third molars is of particular importance, with regard to the relevant age group. To attain a referral database and regression equations for dental age estimation of unaccompanied minors in an Iranian population was the goal of this study. Moreover, determination was made concerning the probability of an individual being over the age of 18 in case of full third molar(s) development.Materials and methodsUsing the scoring system of Gleiser and Hunt, modified by Köhler, an investigation of a cross-sectional sample of 1274 orthopantomograms of 885 females and 389 males aged between 15 and 22 years was carried out. Using kappa statistics, intra-observer reliability was tested. With Spearman correlation coefficient, correlation between the scores of all four wisdom teeth, was evaluated. We also carried out the Wilcoxon signed-rank test on asymmetry and calculated the regression formulae.ResultsA strong intra-observer agreement was displayed by the kappa value. No significant difference (p-value for upper and lower jaws were 0.07 and 0.59, respectively) was discovered by Wilcoxon signed-rank test for left and right asymmetry. The developmental stage of upper right and upper left third molars yielded the greatest correlation coefficient. The probability of an individual being over the age of 18 is 95.6% for males and 100.0% for females in case four fully developed third molars are present. Taking into consideration gender, location and number of wisdom teeth, regression formulae were arrived at.ConclusionUse of population-specific standards is recommended as a means of improving the accuracy of forensic age estimates based on third molars mineralisation. To obtain more exact regression formulae, wider age range studies are recommended.     

Age- and sex-specific morphologic changes in the metaphyseal fossa adjacent to epiphyseal tubercle in children and adolescents without hip disorders

The epiphyseal tubercle plays an important role in epiphyseal stabilization. While the majority of studies have focused on tubercle morphology, there is a paucity of information on the morphological features of the metaphyseal fossa, where the tubercle sits on the metaphysis. The goal of this study was to determine the developmental changes in the capital femoral metaphyseal fossa. Computed tomography of the pelvis from 80 children and adolescents 8-15 years old were used to create three-dimensional models of the proximal femur. Depth, width, length, and surface area of the metaphyseal fossa were measured and the impact of age and sex on fossa morphology was assessed using the linear regression and two-way analysis of variance, respectively. The metaphyseal fossa was located in the posterosuperior quadrant of the metaphysis without any variations in the location with increasing age (P > .1). However, with increasing age, there was a reduction in all metaphyseal fossa measurements including the depth, length, width, and surface area (P < .01). No significant differences were noted for the metaphyseal fossa measurements between males and females (P > .1). The metaphyseal fossa reduces in size from 8 to 15 years of age in a similar fashion in males and females. As the metaphyseal fossa adjacent to the tubercle matches the area where a focal radiolucency has been observed in early slipped capital femoral epiphysis (SCFE), further studies should clarify the mechanisms by which the interlocking interaction of the epiphyseal tubercle and its fossa contributes to or is affected by SCFE.     

Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by axial arthritis in which the genetic-environmental factors seem to be involved in the pathogenesis of the disease. This study was performed to investigate the role of polymorphisms of the programmed cell death 1 (PDCD1) gene on susceptibility to AS. In this study, 161 Iranian patients with AS and 208 normal controls were enrolled; two single-nucleotide polymorphisms (SNPs) of the PDCD1 gene PD-1.3 (G, A) in nucleotide position +7146 of intron 4 and PD-1.9 (C, T) in nucleotide +7625 of exon 5 were studied. Analysis of PD-1.3 revealed that 82% of patients and 79% of controls had GG genotype, while GA and AA genotypes were detected in 17% and 0.6% of patients, respectively, and 20% and 1.4% of controls, respectively. Moreover, the genotype CC (PD-1.9) was present in 92% of patients and 97% of controls. Although these differences were not statistically significant between patients and controls, comparisons of genotypes frequencies in the AS patients, based on human leukocyte antigen (HLA)-B27, revealed that all patients who had CT genotype (PD-1.9) were HLA-B27 positive, whereas 30% of patients with CC genotype were HLA-B27 negative. There was no evidence of association for PDCD1 SNPs with AS in our study, but CT genotype (PD-1.9) seems to be associated with HLA-B27 positivity in the patients with AS.     

Long-term efficacy and safety of interferon α-2a therapy in severe refractory ophthalmic Behcet’s disease

Ophthalmic involvement is the most debilitating complication of Behcet’s disease (BD). The aim of the current study is to report on the efficacy and safety of a long-term use of interferon alpha-2a (IFNα-2a) in the treatment of refractory ophthalmic BD in the Azari population of Iran. We retrospectively analyzed the clinical data of 12 patients with ophthalmic BD who were under IFNα-2a therapy. All these patients had previously been treated unsuccessfully with corticosteroid and at least one conventional immunosuppressive drug. IFNα-2a was administered at a daily dose of 6 million IU (MIU). After controlling the symptoms, a dose of 6 MIU three times per week was applied for 8–12 weeks, and then, a dose of 3 MIU was administered three times per week as a subcutaneous injection. Visual acuity and total inflammatory activity index (TIAI) were used in order to assess the response to the treatment. Response to the treatment and complete eye remission were obtained in 10 (83.3 %) and 7 (58.3 %) patients, irrespectively. Improvement or stabilization of visual acuity was observed in 18 (81.8 %) out of 22 eyes. After a mean period of 29.6 months, the use of IFNa-2a was discontinued in eight (66.7 %) patients. Unaltered vision for 2 years after IFNa-2a discontinuation happened in eight (100 %) patients. IFNa-2a is probably effective and safe in the treatment of refractory sight-threatening ophthalmic BD in the Azari population of Iran.     

Primary report on distribution of tick fauna in Iran

A tick survey was carried out in four different geographical areas of Iran, where the majority of the domestic ruminants in Iran exist. About 1,500 sheep, 1,200 goats and 500 cattle of 12 herds in different provinces lying in the corresponding zones were inspected for tick infestation. The occurrence of ticks on cattle, sheep and goats were 62, 55 and 57%, respectively, with no differences between the zones. The mean number of ticks on each animal was low (10-20 ticks per animal). Ixodid ticks were found throughout the year, whereas the soft tick Ornithodoros sp., which occurred in mountainous area with a significant difference in abundance, showed a clear pattern of seasonality, being generally present from November to March. The largest numbers of adult ixodid ticks were generally present from April to August. Rhipicephalus, Haemaphysalis and Dermacentor ticks occurred in the mountainous area, whereas Boophilus and Ixodes ticks were only present in the Caspian region. Hyalomma were very abundant in each zone but especially in the mountainous area, whereas Ixodes ticks were the minor genus.