A Poroelasticity Theory Approach to Study the Mechanisms Leading to Elevated Interstitial Fluid Pressure in Solid Tumours

Although the mechanisms responsible for elevated interstitial fluid pressure (IFP) in tumours remain obscure, it seems clear that high IFP represents a barrier to drug delivery (since the resulting adverse pressure gradient implies a reduction in the driving force for transvascular exchange of both fluid and macromolecules). R. Jain and co-workers studied this problem, and although the conclusions drawn from their idealized mathematical models offered useful insights into the causes of elevated IFP, they by no means gave a definitive explanation for this phenomenon. In this paper, we use poroelasticity theory to also develop a macroscopic mathematical model to describe the time evolution of a solid tumour, but focus our attention on the mechanisms responsible for the rise of the IFP, from that for a healthy interstitium to that measured in malignant tumours. In particular, we discuss a number of possible time scales suggested by our mathematical model and propose a tumour-dependent time scale that leads to results in agreement with experimental observations. We apply our mathematical model to simulate the effect of “vascular normalization” (as proposed by Jain in Nat Med 7:987–989, 2001) on the IFP profile and discuss and contrast our conclusions with those of previous work in the literature.     

Employment Situation of Parents of Long-Term Childhood Cancer Survivors

Background

Taking care of children diagnosed with cancer affects parents’ professional life. The impact in the long-term however, is not clear. We aimed to compare the employment situation of parents of long-term childhood cancer survivors with control parents of the general population, and to identify clinical and socio-demographic factors associated with parental employment.

Methods

As part of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to parents of survivors aged 5–15 years, who survived ≥5 years after diagnosis. Information on control parents of the general population came from the Swiss Health Survey (restricted to men and women with ≥1 child aged 5–15 years). Employment was categorized as not employed, part-time, and full-time employed. We used generalized ordered logistic regression to determine associations with clinical and socio-demographic factors. Clinical data was available from the Swiss Childhood Cancer Registry.

Results

We included 394 parent-couples of survivors and 3’341 control parents (1’731 mothers; 1’610 fathers). Mothers of survivors were more often not employed (29% versus 22%; p_trend = 0.007). However, no differences between mothers were found in multivariable analysis. Fathers of survivors were more often employed full-time (93% versus 87%; p_trend = 0.002), which remained significant in multivariable analysis. Among parents of survivors, mothers with tertiary education (OR = 2.40, CI:1.14–5.07) were more likely to be employed. Having a migration background (OR = 3.63, CI: 1.71–7.71) increased the likelihood of being full-time employed in mothers of survivors. Less likely to be employed were mothers of survivors diagnosed with lymphoma (OR = 0.31, CI:0.13–0.73) and >2 children (OR = 0.48, CI:0.30–0.75); and fathers of survivors who had had a relapse (OR = 0.13, CI:0.04–0.36).

Conclusion

Employment situation of parents of long-term survivors reflected the more traditional parenting roles. Specific support for parents with low education, additional children, and whose child had a more severe cancer disease could improve their long-term employment situation.     

Multiple effects of linolenic acid addition to pea thylakoids

The addition of linolenic acid to thylakoids produces various pH-dependent effects. We have demonstrated a binding site near the Photosystem (PS) II center with a pK_a of 6.5: when linolenic acid is unprotonated it induces in the dark a rise of the initial fluorescence level, the latter being similar to the maximum fluorescence obtained during illumination of untreated thylakoids. The comparison of the fluorescence lifetimes in the presence and absence of linolenic acid leads us to conclude that the charge stabilisation on the primary acceptor, Q, is prevented by linolenic acid. A second binding site on the protein carrying B, the secondary acceptor of PS II, has also been demonstrated for linolenic acid. It has a 3-(3,4-dichlorophenyl)-1,1-dimethylurea-type effect both in the protonated and unprotonated forms. Finally, measurements of electrophoretic mobility of the thylakoids indicate several other sites of linolenic acid inclusion with an average pK_a of 5.7. At alkaline pH the presence of unprotonated linolenic acid increases the charge density on the membrane. As a result a higher concentration of divalent cations is needed to obtain fluorescence and stacking changes than for untreated thylakoids. The presence, at acidic pH values, of the unprotonated form of linolenic acid leads to the inhibition of cation-induced fluorescence changes, probably by preventing the movement of chlorophyll-protein complexes in the membrane.     

The mechanism of glucose 6-phosphate–d-myo-inositol 1-phosphate cyclase of rat testis. The involvement of hydrogen atoms

Comparison of the initial (3)H/(14)C ratios in specifically labelled d-glucose 6-phosphates with the final ratios in myo-inositol produced by glucose 6-phosphate-d-myo-inositol 1-phosphate cyclase from rat testis showed that, during the conversion, the hydrogen atoms at C-1 and C-3 were fully retained, one hydrogen atom was lost from C-6, and that at C-5 was apparently retained to the extent of 80-90%. The loss of (3)H could not be stimulated by addition of unlabelled NADH, and when unlabelled substrate was used (3)H from [(3)H]NADH and [(3)H]water was not incorporated. Treatment of the enzyme with charcoal abolished the activity, and this was restored to 25-50% of the original activity by NAD(+). The charcoal-treated enzyme again apparently gave 85% retention of hydrogen with [5-(3)H]glucose 6-phosphate as substrate in the presence of NAD(+) alone, but the retention was decreased to 65% with excess of NADH. The results are interpreted as indicating that the cyclization proceeds by an aldol condensation in which C-5 is oxidized by NAD(+) in a tightly-bound ternary complex, and that the apparent loss of (3)H when untreated enzyme is used is due to an isotope effect. It is suggested that after treatment with charcoal some exchange of NADH with an external pool may take place.     

The recombinant congenic strains—a novel genetic tool applied to the study of colon tumor development in the mouse

The development of tumors in mice is under multigenic control, but, in spite of considerable efforts, the identification of the genes involved has so far been unsuccessful, because of the insufficient resolution power of the available genetic tools. Therefore, a novel genetic tool, the RC (Recombinant Congenic) strains system, was designed. In this system, a series of RC strains is produced from two inbred strains, a background strain and a donor strain. Each RC strain contains a different small subset of genes from the donor strain and the majority of genes from the background strain. As a consequence, the individual genes of the donor strain which are involved in the genetic control of a multigenic trait, become separated into different RC strains, where they can be identified and studied individually. One of the RC strains series which we produced is made from the parental strains BALB/cHeA (background strain) and STS/A (donor strain). We describe the genetic composition of this BALB/cHeA-C-STS/A (CcS/Dem) series and show, using 45 genetic autosomal markers, that it does not deviate from the theoretical expectation. We studied the usefulness of the CcS/Dem RC strains for analysis of the genetics of colon tumor development. The two parental strains, BALB/cHeA and STS/A, are relatively resistant and highly susceptible, respectively, to the induction of colon tumors by 1,2-dimethylhydrazine (DMH). The individual RC strains differ widely in colon tumor development after DMH treatment; some are highly susceptible, while others are very resistant. This indicates that a limited number of genes with a major effect are responsible for the high susceptibility of the STS strain. Consequently, these genes can be mapped by further analysis of the susceptible RC strains. The differences between the RC strains were not limited to the number of tumors, but the RC strains differed also in size of the tumors and the relative susceptibility of the two sexes. Our data indicate that the number of tumors and the size of tumors are not controlled by the same genes. The genetics of these different aspects of colon tumorigenesis can also be studied by the RC strains. The DMH-treated mice of the parental strains and the RC strains also developed anal tumors and haemangiomas in varying numbers. The strain distribution pattern (SDP) of susceptibility for each of the three types of tumors induced by DMH is different, indicating that development of these tumors is under control of different, largely non-overlapping, sets of genes. Thus, with a single series of RC strains, genes involved in tumorigenesis in various organs and tissues can be studied separately. These results indicate that the novel genetic tool, the RC strain system, offers new possibilities for analysis of the multigenic control of tumor development.     

Role of Heme–Hemopexin in Human T-Lymphocyte Proliferation

Heme–hemopexin supports and stimulates proliferation of human acute T-lymphoblastic (MOLT-3) cells, suggesting the participation of heme in cell growth and division. MOLT-3 cells express approximately 58,000 hemopexin receptors per cell (apparent K_d20 nM), of which about 20% are on the cell surface. Binding is dose- and temperature-dependent, and growth in serum-free IMDM medium is stimulated by 100–1000 nMheme–hemopexin, consistent with the high affinity of the receptor for hemopexin, and maximal growth is seen in response to 500 nMcomplex. Growth was similar in defined minimal medium supplemented with either low concentrations of heme–hemopexin or iron-transferrin, and either of these complexes were about 80% as effective as a serum supplement. Heme–hemopexin, but not apo–hemopexin, reversed the growth inhibition caused by desferrioxamine showing that heme–iron derived from heme catabolism is used for cell growth. Cobalt-protoporphyrin (CoPP)–hemopexin, which binds to the receptor but is not transported intracellularly [Smithet al.,(1993)J. Biol. Chem.268, 7365], also stimulated cell proliferation in serum-free IMDM but did not “rescue” the cells from desferrioxamine. Furthermore, CoPP–hemopexin effectively competed for the hemopexin receptor with heme–hemopexin and diminished its growth stimulatory effects. In addition, protein kinase C (PKC) is translocated to the plasma membrane within 5 min after heme–hemopexin is added to the medium, reaches maximum activity within 5–10 min, and declines to unstimulated levels by 30 min. Heme–hemopexin and CoPP-hemopexin both augmented MOLT-3 cell growth stimulated by serum. Thus, heme–hemopexin not only functions as an iron source for T-cells but occupancy of the hemopexin receptor itself triggers signaling pathway(s) involved in the regulation of cell growth. The stimulation of growth of human T-lymphocytes by heme–hemopexin is likely to be a physiologically relevant mechanism at sites of injury, infection, and inflammation.