The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes

The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell–cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression.     

Przedtransplantacyjne czynniki ryzyka reaktywacji zakażenia wirusem cytomegalii po przeszczepieniach allogenicznych komórek hematopoetycznych u dzieci i młodych dorosłych

BackgroundCytomegalovirus (CMV) reactivation remains one of the most frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT).MethodsAn analysis of the pre-transplant risk factors of CMV reactivation was performed in 98 patients aged 0.5–22 years (median 10.5) undergoing allogeneic HSCT. CMV reactivation was tested by assessing viral load using PCR method. Following factors were analyzed: type of conditioning, graft source, donor type, use of T-depletion and CMV-serostatus of the donor and recipient. Each factor was assigned from 0 to 2 points. Based on total score for each patient, CMV reactivation risk scale was developed, and two groups with low (LR) and high (HR) risk were determined.ResultsCMV reactivation was seen in 25 patients (24.5%). The significant risk factors for CMV reactivation were: CMV-positive recipient (p<0.001), unrelated donor (p<0.002), use of ATG (p<0.002) and PBSC (p<0,01). In the HR group the incidence of reactivation CMV was significantly higher than in LR group (47.8% vs. 5.4%, p<0.001).ConclusionsCMV seropositivity of the recipient was an independent predictor factor of CMV reactivation. The use of risk point scale of CMV reactivation allows for identification of patients with the higher risk of CMV reactivation.     

Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.     

Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression

Granot E, Loewenthal R, Jakobovich E, Gazit E, Sokal E, Reding R. Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression.
Pediatr Transplantation 2012: 16: E1–E4. © 2010 John Wiley & Sons A/S. Abstract: We report long‐term (seven yr) immunological tolerance in a 16‐yr‐old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post‐transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression‐free solid organ transplantation from the same donor.     

BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland

Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.     

Adhesion molecules and their ligands in nasal polyps of aspirin-hypersensitive patients.

BACKGROUND: Chronic inflammation with tissue eosinophilia plays a key role in the pathogenesis of asthma and nasal polyps in patients with aspirin hypersensitivity. OBJECTIVE: To evaluate the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule I (ICAM-1) and their ligands (the integrins lymphocyte function-associated antigen 1 and very late-activation antigen 4 [VLA-4]) in nasal polyps of patients with aspirin hypersensitivity compared with aspirin-tolerant individuals. METHODS: Immunohistochemical studies were performed using a peroxidase method and monoclonal antibodies on 6-microm-thick cryostat sections cut from frozen polyps collected during elective surgery from 21 aspirin-sensitive and 23 aspirin-tolerant patients. RESULTS: The mean +/- SD values of the semiquantitatively evaluated immunoexpression of ICAM-1, VCAM-1, and VLA-4 were significantly increased in patients with aspirin hypersensitivity compared with aspirin-tolerant patients (1.7 +/- 0.8 vs 0.9 +/- 0.8, P < .003; 1.8 +/- 0.8 vs 0.8 +/- 0.8, P < .001; and 2.2 +/- 0.7 vs 1.3 +/- 0.7, P < .001, respectively), whereas the mean +/- SD values of the expression of lymphocyte function-associated antigen 1 did not differ significantly (2.4 +/- 0.5 vs 2.2 +/- 0.9; P = .57). We found a correlation between the immunoexpression of VCAM-1 and its ligand VLA-4 in all studied tissue samples (r = 0.4; P < .02). CONCLUSIONS: In nasal polyps of aspirin-hypersensitive patients, up-regulation of the adhesion molecules ICAM-1 and VCAM-1 and the integrin VLA-4 may play an important role in the development of chronic eosinophilic inflammation.     

Coombs-positive giant cell hepatitis of infancy: effect of steroids and azathioprine therapy

An 8-month-old boy and a 7-month-old girl presented with an acute, Coombs-positive auto-immune haemolytic anaemia and severe hepatitis. The clinical manifestations were pallor, jaundice and hepatomegaly. The liver histology revealed diffuse giant cell transformation and extensive necrosis with central-portal bridging. Combined immunosuppressive regimen with steroids and azathioprine led to prolonged clinical and biological remission with a respective 2 years and 6 months follow up. The girl, however, after 7 months developed a progressive encephalopathy of unknown aetiology, while liver and haematological disease were still under control. She died subsequently from severe recurrentseizures. We conclude that acute Coombs-positive giant cell hepatitis of infancy can be improved by sustained immunosuppressive therapy.     

Fulminant hepatitis B in an infant born to a hepatitis Be antibody positive,DNA negative carrier.

A boy was born to a mother who was a chronic hepatitis B virus (HBV) carrier. She was hepatitis Be (HBe) antibody positive and HBe antigen and HBV-DNA negative. The boy had not received hepatitis B vaccine and died from fulminant hepatitis at 3 months of age. This case demonstrates the need to vaccinate babies of HBe antibody positive, HBe antigen negative carriers.     

Prenatal exposure to ethanol in rats: effects on postnatal maturation of the small intestine and liver.

To examine the effects of prenatal exposure to ethanol on postnatal development of small intestinal and liver functions, female rats were accustomed to increasing amounts of ethanol (10 to 25%, vol/vol) in tap water for 1 mo. During pregnancy, ethanol-fed dams had higher daily caloric intake and similar weight gain compared with controls. In ethanol offspring, neonatal mortality was 28.9% compared to 0% in controls. Although ethanol had been withdrawn at birth, pups issued from ethanol-treated mothers showed at 5 and 10 d postpartum decreased values of body weight, jejunal and ileal weights, and intestinal DNA concentration per unit of length, as well as lower specific and total activities in lactase and maltase, compared with controls. DNA synthesis rates, measured by the incorporation of [3H]thymidine into mucosal DNA, were also significantly (-20 to -34%, p < 0.01) depressed in the jejunum and ileum of ethanol pups at 5 and 10 d of age. All these parameters returned to control levels by d 15 postpartum. Electron microscopy of jejunal mucosal samples at 5, 10, and 15 d of age revealed that ethanol pups differed from controls by a fetal-like immature aspect of the enterocytes, which persisted up to d 15. The ontogenic upsurge in sucrase and the decline in lactase occurred at weaning with the same chronology in both groups, but the level reached by sucrase activity was about 50% lower in alcohol offspring than in controls. Except for moderate steatosis, the ultrastructure of hepatocytes was unaltered in sucklings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis

Orthotopic liver transplantation (OLT) has been proposed to treat patients with type IV glycogenosis because of early progressive cirrhosis. Reports have shown absence of disease progression in other organs after OLT and even regression of cardiac amylopectin infiltration in one case. We describe a 15-month-old child in whom a liver transplant was performed for type IV glycogenosis. There were no clinical signs of extrahepatic disease before OLT. Nine months later, the patient developed progressive cardiac insufficiency and died from cardiac failure. Because of massive amylopectin deposits, decreased myofibrils in cardiac cells, and exclusion of other causes of cardiac failure, death was attributed to amylopectinosis. Our observation contrasts with the Pittsburgh experience and suggests that cardiac amylopectionosis may progress after OLT.