Preoperative mannan-binding lectin pathway and prognosis in colorectal cancer

Purpose: Deficiency of the mannan-binding lectin (MBL) pathway of innate immunity is associated with increased susceptibility to infections. In patients with colorectal cancer (CRC), postoperative infection is associated with poor prognosis. The aim of the present study was to evaluate (1) the relation between the MBL pathway and postoperative infectious complications and survival of patients resected for CRC, and (2) the role of MBL in acute phase response compared to C-reactive protein (CRP). Methods: Preoperative MBL concentration, MBL-associated serine protease (MBL/MASP) activity and CRP were determined in serum from 611 patients and 150 healthy controls. The patients were observed for 8 years. Postoperative infections, recurrence and survival were recorded. Results: The MBL pathway components were increased in the patients compared with the healthy controls (p<0.0001). Low MBL levels were predictive of pneumonia (p=0.01), and pneumonia (n=87) was associated with poor survival (p=0.003; HR=1.5; 95% CI, 1.1 to 1.9). MBL and MBL/MASP activity showed no correlation with CRP (Spearmans =0.02; 95% CI, –0.06 to 0.10). Conclusion: Low preoperative MBL levels are predictive of pneumonia, which is associated with poorer survival. MBL concentration and MBL/MASP activity was not predictive of other postoperative infections or long-term prognosis, and showed no correlation with CRP.     

Spontaneous T-cell responses against peptides derived from the Taxol resistance–associated gene-3 (TRAG-3) protein in cancer patients

Expression of the cancer-testis antigen Taxol resistance–associated gene-3 (TRAG-3) protein is associated with acquired paclitaxel (Taxol) resistance, and is expressed in various cancer types; e.g., breast cancer, leukemia, and melanoma. Thus, TRAG-3 represents an attractive target for immunotherapy of cancer. To identify HLA-A*02.01–restricted epitopes from TRAG-3, we screened cancer patients for spontaneous cytotoxic T-cell responses against TRAG-3–derived peptides. The TRAG-3 protein sequence was screened for 9mer and 10mer peptides possessing HLA-A*02.01–binding motifs. Of 12 potential binders, 9 peptides were indeed capable of binding to the HLA-A*02.01 molecule, with binding affinities ranging from strong to weak binders. Subsequently, lymphocytes from cancer patients (9 breast cancer patients, 12 melanoma patients, and 13 patients with hematopoietic malignancies) were analyzed for spontaneous reactivity against the panel of peptides by ELISpot assay. Spontaneous immune responses were detected against 8 epitope candidates in 7 of 9 breast cancer patients, 7 of 12 melanoma patients, and 5 of 13 patients with hematopoietic malignancies. In several cases, TRAG-3–specific CTL responses were scattered over several epitopes. Hence, no immunodominance of any single peptide was observed. Furthermore, single-peptide responses were detected in 2 of 12 healthy HLA-A2⁺ donors, but no responses were detectable in 9 HLA-A2^– healthy donors or 4 HLA-A2^– melanoma patients. The identified HLA-A*02.01–restricted TRAG-3–derived epitopes are targets for spontaneous immune responses in breast cancer, hematopoietic cancer, and melanoma patients. Hence, these epitopes represent potential target structures for future therapeutic vaccinations against cancer, possibly appropriate for strategies that combine vaccination and chemotherapy; i.e., paclitaxel treatment.     

GDNF and GFRalpha1 promote differentiation and tangential migration of cortical GABAergic neurons

Cortical GABAergic neurons are generated in the ventral telencephalon and migrate dorsally into the cortex following a tangential path. GDNF signaling via GFRalpha1 was found to promote the differentiation of ventral precursors into GABAergic cells, enhancing their neuronal morphology and motility. GDNF stimulated axonal growth in cortical GABAergic neurons and acted as a potent chemoattractant of GABAergic cells. These effects required GFRalpha1 but neither RET nor NCAM, the two transmembrane signaling receptors known for GDNF. Mutant mice lacking GDNF or GFRalpha1, but neither RET nor NCAM, showed reduced numbers of GABAergic cells in the cerebral cortex and hippocampus. We conclude that one of the normal functions of GDNF signaling via GFRalpha1 in the developing brain is to promote the differentiation and migration of cortical GABAergic neurons. The lack of involvement of RET or NCAM in these processes suggests the existence of additional transmembrane effectors for GDNF.     

Biodiversity correlates with regional patterns of forest litter pools

We compared litter pools of more than 1,000 forests differing in tree species diversity over a large scale in Catalonia (NE Spain). Monospecific forests always had smaller litter pools than mixed (from 2 to 5 tree species) forests. Whether there was a positive effect beyond two species mixtures depended on the species and functional identity of the dominant tree species. In sclerophyllous forests the positive effect of diversity was a step-function from one to more species. However, in conifers, litter pools increased constantly with tree diversity. The identity of the dominant tree species and functional type had also a significant effect on litter pools. For instance, forests dominated by sclerophyllous tree species had larger litter pools than forests dominated by deciduous and conifer tree species. When other forest structure parameters (i.e. tree basal area, wood production, successional stage, shrub cover and leaf area index) and environmental factors (i.e. mean annual temperature, mean annual precipitation, annual evapotranspiration and hillside position) where included in the analysis only leaf area index, basal area, wood production and mean temperature influenced litter pools positively. Our analysis emphasizes that at the regional scale, the litter compartment can be as influenced by biodiversity components as by other forest structure and climate components. In mixed forests, species and functional identity of the trees determine whether litter pools increase with tree diversity.     

Connection between rod bivalents and incomplete meiotic association at NORs in Hordeum marinum Huds

The hypothesis of a connection between rod bivalent formation and incomplete meiotic association at NORs of SAT-chromosomes of H. marinum is supported. PMCs of H. marinum ssp. gussoneanum (2x), two diploid ssp. marinum × ssp. gussoneanum (2x) hybrids and two ssp. gussoneanum (4x) × Secale cereale hybrids at metaphase I (M-I) were analyzed by in situ hybridization. The probe pTa71 labelled rDNA sites at NORs of a single pair of homologous or near-homologous SAT-chromosomes of H. marinum in each material. In the three diploids, M-I was regular with ring bivalents and one or a few rods (av.13.52 bound arms cell(-1) ). More rod bivalents than the expected one out of seven, i.e. 30, 67 and 89% included rDNA-carrying chromosomes. Corresponding bound short arm frequencies were 0.89, 0.72 and 0.52, while long arms and arms of other chromosomes presented complete or near- complete association. The two heterogenomic hybrids had a less regular M-I (av. 8.04 bound arms cell(-1) ) including 20% rDNA-carrying rods with bound arm frequencies of 0.29 in short and 0.87 in long arms. Positions of chromosome associations were established in all 150 rDNA-carrying bivalents. In 77 bivalents with short arm associations, 4% of these occurred proximally to, none at, and 96% distally to rDNA sites, i.e. in satellites. In 143 bivalents with long arm associations, 83% occurred at interstitial and 17% at terminal positions. The observations combine increased frequency of rDNA-carrying rods with decreased frequency of association at NOR regions of SAT-chromosomes. The basis for the relationship is discussed.