B7-h4 is highly expressed in ductal and lobular breast cancer.

PURPOSE: This study was designed to investigate the expression of B7-H4 protein, a member of the B7 family that is involved in the regulation of antigen-specific immune responses, in normal breast and in primary and metastatic breast carcinomas. EXPERIMENTAL DESIGN: Archival formalin-fixed tissue blocks from breast cancers and normal somatic tissues were evaluated for B7-H4 expression by immunohistochemistry with manual and automated image analysis. The proportion of B7-H4-positive cells and the intensity of B7-H4 staining were compared with histologic type, grade, stage, hormone receptor status, and HER-2/neu status. RESULTS: B7-H4 was detected in 165 of 173 (95.4%) primary breast cancers and in 240 of 246 (97.6%) metastatic breast cancers. B7-H4 staining intensity was greater in invasive ductal carcinomas [24.61 relative units (RU)] and in invasive lobular carcinomas (15.23 RU) than in normal breast epithelium (4.30 RU, P = 0.0003). Increased staining intensity was associated with negative progesterone receptor status (P = 0.014) and history of neoadjuvant chemotherapy (P = 0.004), and the proportion of B7-H4-positive cells was associated with negative progesterone receptor (P = 0.001) and negative HER-2/neu (P = 0.024) status. However, there was no statistically significant relationship between the proportion of B7-H4-positive cells or staining intensity and grade, stage, or other clinicopathologic variables. Low levels of B7-H4 expression were also detected in epithelial cells of the female genital tract, lung, pancreas, and kidney, but B7-H4 was generally absent in most other normal somatic tissues. CONCLUSIONS: The nearly ubiquitous expression of B7-H4 in breast cancer, independent of tumor grade or stage, suggests a critical role for this protein in breast cancer biology.     

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.     

Probiotic E.faecalis — adjuvant therapy in children with recurrent rhinosinusitis

Sinusitis is a frequent complication of respiratory tract infections. Probiotics are perceived to be useful in infections, allergies, and inflammations. Our prospective trial stratified 204 children with recurrent rhinosinusitis by age (2–11 years, 54m:64f; 12–18 years, 39m:47f) and assigned them to standard treatment (antibiotics, anticongestants) or additional 60 days Symbioflor-1 (SF1; Enterococcus faecalis 1.5–4.5x10⁷ CFU). The number of sinusitis episodes was lower in SF1-treated patients (2.52±0.91) than among controls (3.27±1.36; p=0.01). Mean duration of the first sinusitis episode was 11.9±8.6 days with SF1, whereas it was 16.1±12.9 days in the younger controls (p=0.023) and 9.86±5.05 days in the elder controls (n.s.). Duration of subsequent sinusitis episodes was also shorter in SF1 patients (15.2±13.6 days) compared with controls (22.7±14.8 days; p=0.030). No adverse events were observed. Probiotic Enterococcus faecalis adjuvant to conventional therapy can reduce the number and duration of rhinosinusitis episodes in children and adolescents.     

Biochemical Binding and Distribution of Protactinium-233 in the Rat

Summary

Following intravenous injection into male Sprague–Dawley rats ²³³Pa, like other elements, deposits predominantly in the skeleton (ca. 70–80 per cent), but unlike Pu and Am the liver deposition of ²³³Pa is low, about 2–3 per cent between 1 and 7 days. About 99 per cent of the injected ²³³Pa is lost from the plasma compartment in 3 days, a clearance comparable to that of Pu but much slower than that of Np, Am or Cm. On entering the liver cell cytosol ²³³Pa is bound rapidly to an unidentified protein of molecular mass 200 kDa and to a protein of 80 kDa, which is probably transferrin. Within a few hours the metal migrates to bind to a protein of > 400 kDa which has been tentatively identified as ferritin. Some ²³³Pa remains bound to small ligands until virtually all the intracellular ²³³Pa has been deposited in the lysosomes, or to a lesser extent in some other, as yet, unidentified organelles.     

Right heart function in impaired left ventricular diastolic function: 2D speckle tracking echocardiography–based and Doppler tissue imaging–based analysis of right atrial and ventricular function

Aim

The aim of our study was to describe right atrial (RA) and right ventricular (RV) function, assessed by Doppler tissue imaging and 2D speckle tracking echocardiography (2DSTE), in women with signs of early impaired left ventricular diastolic function (DD).

Methods and Results

In a cross‐sectional trial, standard parameters of diastolic and right heart function were investigated in 438 women of the Berlin Female Risk Evaluation (BEFRI) study. In a subset of women, average peak systolic RA strain (RAS), as well as the average peak systolic RV strain of the free wall (RVS free wall) and of all RV segments (average RV strain; RVS Avg), was analyzed using 2DSTE. Compared to women with normal diastolic function (DD0), RAS, RVS free wall and RVS Avg were significantly reduced in DD (43.1% ± 11.9%, ?26.7% ± 5.6%, and ?23.3% ± 3.5% in DD0; vs 35.1% ± 10.4%, ?23.9% ± 5.5%, and ?20.6% ± 3.8% in DD; P < .01). Peak RV myocardial velocity (RV‐IVV) and acceleration during isovolumetric contraction (RV‐IVA) were markedly higher in DD (15.0 ± 3.9 cm/s and 3.1 ± 1.0 m/s² in DD vs 11.9 ± 3.2 cm/s and 2.8 ± 0.8 m/s² in DD0; P < .05). RAS and RV‐IVV were significantly associated with DD after adjustment to age, BMI, and left atrial strain in multivariate regression analysis.

Conclusion

Systolic right heart function is significantly altered in DD. DTI as well as 2DSTE constitute sensitive echocardiographic tools that enable the diagnosis of impaired right heart mechanics in early‐staged DD.     

In vitro and in vivo effects of JAK2 inhibition in chronic myelomonocytic leukemia

In chronic myelomonocytic leukemia (CMML), colony‐forming units granulocyte/macrophage (CFU‐GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM‐CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU‐GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU‐GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU‐GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU‐GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.