Coinheritance of sickle cell anemia and hereditary spherocytosis

To date only three siblings with coinheritance of sickle cell anemia (SCA) and hereditary spherocytosis (HS) have been reported. We here describe a 17-year-old boy who experienced episodes of hemolysis and had a large spleen. The diagnosis of SCA was confirmed by hemoglobin electrophoresis (HbS 88.9%) and genetic analysis (homozygote HbSS mutation). The diagnosis of HS was established by an osmotic fragility test, performed twice. A splenectomy was performed, and following surgery the hemoglobin concentration was maintained between 9 and 11 g/dl without further transfusion requirements. This patient was the fourth reported case with co-existence of two different genetically transmitted hemolytic anemias.     

The relationship between plasma MMP-9 and TIMP-2 levels and intraocular pressure elevation in diabetic patients after intravitreal triamcinolone injection

PURPOSE: To find out the relationship between steroid-induced intraocular pressure (IOP) rise and the plasma levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-2 (TIMP-2) in diabetic patients who underwent intravitreal triamcinolone acetonide (IVTA) injection for the treatment of diabetic macular edema. SUBJECTS AND METHODS: A total of 34 patients with diabetic macular edema who were treated with IVTA and 17 healthy subjects who served as control group for plasma MMP and TIMP levels were participated. Before IVTA treatment, patients and control subjects underwent complete ophthalmologic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, IOP measurement with Goldmann applanation tonometry, and indirect ophthalmoscopy; and peripheral blood samples were collected from each study participants. Plasma levels of MMP-9, TIMP-2, and HbA1c levels were measured. Patients were seen 1, 6, 12, and 24 weeks after treatment and then every 6 months for up to 1 year for probable IOP rise. Patients were divided into 2 groups as having nonproliferative or proliferative diabetic retinopathy. These 2 groups were further classified according to their IOP levels as normal or elevated IOP (>21 mm Hg). RESULTS: The mean age of diabetic group of patients (n=34) and healthy control subjects (n=17) were 57.6+/-10.2 years (range: 22 to 70 y) and 53.1+/-10.3 years (range: 29 to 68 y), respectively. Seventeen (50%) diabetic patients had developed elevated IOP after a mean 2.2 months after IVTA injection. MMP-9 and TIMP-2 levels were found to be significantly higher in the diabetic groups with and without elevated IOP when compared with control group (P<0.001). MMP-9/TIMP-2 did not change significantly among the groups. Logistic regression analysis showed that only higher plasma TIMP-2 levels increase the risk of IOP elevation after IVTA injection in proliferative diabetic retinopathy (odds ratio=1.06, P<0.05). No significant relationship was found between IOP rise and HbA1c levels. CONCLUSIONS: The high levels of TIMP in diabetic patients might have a role on steroid-induced IOP rise. The key pathogenetic events that up-regulate TIMP levels should be investigated in steroid IOP rise in diabetics.     

Decreased TGFβ signaling and increased COX2 expression in high risk women with increased mammographic breast density

High mammographic density is associated with a increased risk of breast cancer. We hypothesized that specific pathways exist that are associated with increased mammographic density, and may therefore be used to identify potential targets for chemoprevention. Histologically confirmed normal breast tissue was collected from women undergoing breast surgery who had available demographic data and mammograms for review. Women with low versus high mammographic breast density were compared. Differentially expressed genes using Affymetrix HG U133Plus2 chips were identified in dense versus non-dense tissue. Immunohistochemical analysis (IHC) of estrogen receptor, progesterone receptor, Ki67, and COX2 expression was performed. About 66 women were identified, 28 (42%) had high, and 38 (58%) had low mammographic density. About 73 genes had differential expression between normal breast tissue with high and low mammographic density (P < 0.001, fold change ≥1.5with a low false discovery rate (<10%). Network and canonical pathway analysis indicated decreased TGFβ signaling (TGFBR2, SOS, SMAD3, CD44 and TNFRSF11B) in dense breast tissue relative to non-dense breast. By IHC, only COX2 expression in the stroma was statistically significant on multivariate analysis. TGFβ ligands are currently the only growth factors known to prevent mammary epithelial cell proliferation. TGFβ signaling has been reported to be inhibited by COX-2, and these molecules are highly differentially expressed in individuals at high risk of developing breast cancer. These results strongly suggest that COX2 inhibition should be investigated for breast cancer prevention despite possible increase in cardiovascular risk.     

Maspin,VEGF and p53 Expression in Small Biopsies of Primary Advanced Lung Cancer and Relationship with Clinicopathologic Parameters

Maspin, one of the serine protease inhibitors, has been shown to inhibit tumor progression and metastasis. We aimed to investigate maspin, p53 and VEGF expression in patients with squamous cell carcinoma (SCC), adenocarcinoma (AC) and small cell lung carcinoma (SCLC). The study included 28 SCC, 18AC, 17 SCLC biopsy samples. We used the streptavidin biotin immunoperoxidase method to test for maspin, p53 and VEGF antibodies. Medical records of these patients were reviewed from archival files. Cytoplasmic maspin expression was detected in 89.3%, 77.8%, 52.9% of SCC, AC and SCLC, respectively. The rate was significantly higher in non-small cell lung cancer (NSCLC) and SCC than SCLC (p = 0.013, p = 0.021, respectively). The mean percentages of maspin expression were significantly higher in NSCLC, SCC and AC than in SCLC (p = 0.0001, p = 0.0001, p = 0.038, respectively). In ACs, maspin and p53 expressions were correlated, although this was not statistically significant (p = 0.053, r = 0.464), and maspin positive cases had a significantly higher T status compared to negative cases (p = 0.036). In SCC, the stage of disease was positively correlated with p53 (p = 0.007, r = 0.536) and negatively correlated with VEGF expression (p = 0.013, r = −0.498). Multivariate analysis demonstrated that stage of disease was a significant independent prognostic parameter in NSCLC (95% confidence interval: 1.067–3.969; p = 0.031). Although maspin expression is higher in SCC and AC, and is related with higher T status in AC, our data did not indicate its prognostic significance. Larger scale studies are needed to reveal the exact role of maspin in lung cancer pathogenesis.     

Study of FHIT and WWOX expression in mucoepidermoid carcinoma and adenoid cystic carcinoma of salivary gland

Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are salivary gland neoplasms with divergent morphological features and clinical behavior. ACC is a basaloid tumor whereas MEC is a glandular epithelial neoplasm. FHIT and WWOX are tumor suppressor genes that encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3, respectively. In previous studies, we have shown concordant loss of Fhit and Wwox expression in breast cancer, with significantly more frequent loss in cancers of basal-like phenotype. To determine if there is a similar association in salivary gland neoplasms, we designed a study of MEC and ACC of salivary gland on tissue microarrays (TMA). TMAs were constructed from 25 MEC and 19 ACC of salivary gland. Fhit and Wwox protein expression was assessed by immunohistochemical staining of cores on TMAs. Correlations among immunohistochemical markers and histological type were determined by statistical analyses. Significantly reduced Fhit and Wwox expression was observed in ACC (p = 0.002 and p < 0.001, respectively). The results suggest that, as for breast cancer, loss of Fhit and Wwox expression might have a role in the pathogenesis of basaloid differentiation in salivary gland neoplasms; alternatively, differences in chromatin structure at chromosome fragile regions might make fragile genes more accessible to DNA damage and rearrangement early during preneoplastic stages of basaloid cancers. Studies of basaloid tumors of other organ systems may show similar results and these findings may have implications for treatment modalities designed for basal-like tumors.