Incidence and time trends of childhood lymphomas: findings from 14 Southern and Eastern European cancer registries and the Surveillance,Epidemiology and End Results,USA

Purpose

To describe epidemiologic patterns of childhood (0–14 years) lymphomas in the Southern and Eastern European (SEE) region in comparison with the Surveillance, Epidemiology and End Results (SEER), USA, and explore tentative discrepancies.

Methods

Childhood lymphomas were retrieved from 14 SEE registries (n = 4,702) and SEER (n = 4,416), diagnosed during 1990–2014; incidence rates were estimated and time trends were evaluated.

Results

Overall age-adjusted incidence rate was higher in SEE (16.9/10⁶) compared to SEER (13.6/10⁶), because of a higher incidence of Hodgkin (HL, 7.5/10⁶ vs. 5.1/10⁶) and Burkitt lymphoma (BL, 3.1 vs. 2.3/10⁶), whereas the incidence of non-Hodgkin lymphoma (NHL) was overall identical (5.9/10⁶ vs. 5.8/10⁶), albeit variable among SEE. Incidence increased with age, except for BL which peaked at 4 years; HL in SEE also showed an early male-specific peak at 4 years. The male preponderance was more pronounced for BL and attenuated with increasing age for HL. Increasing trends were noted in SEER for total lymphomas and NHL, and was marginal for HL, as contrasted to the decreasing HL and NHL trends generally observed in SEE registries, with the exception of increasing HL incidence in Portugal; of note, BL incidence trend followed a male-specific increasing trend in SEE.

Conclusions

Registry-based data reveal variable patterns and time trends of childhood lymphomas in SEE and SEER during the last decades, possibly reflecting diverse levels of socioeconomic development of the populations in the respective areas; optimization of registration process may allow further exploration of molecular characteristics of disease subtypes.

     

Class 1A PI3K regulates vessel integrity during development and tumorigenesis

PI3K is important in the regulation of growth, proliferation, and survival of tumor cells. We show that class 1A PI3K is also critical in the tumor microenvironment by regulating the integrity of the tumor vasculature. Using Tie2Cre-mediated deletion of the PI3K regulatory subunits (p85alpha, p55alpha, p50alpha, and p85beta), we generated mice with endothelial cell-specific loss of class 1A PI3K. Complete loss of all subunits caused acute embryonic lethality at E11.5 due to hemorrhaging, whereas retention of a single p85alpha allele yielded viable mice that survived to adulthood. These heterozygous mice exhibited no vascular defects until challenged with a pathological insult, such as tumor cells or high levels of VEGF. Under these pathological conditions, heterozygous mice exhibited localized vascular abnormalities, including vessel leakage and the inability to maintain large vessels, which caused a deceleration of tumorigenesis. Furthermore, we show that a PI3K inhibitor can mimic the effects of class 1A PI3K loss, which suggests that targeting class 1A PI3K may be a promising therapy for blocking tumor angiogenesis.     

Unraveling the molecular basis of subunit specificity in P pilus assembly by mass spectrometry

P pili are multisubunit fibers essential for the attachment of uropathogenic Escherichia coli to the kidney. These fibers are formed by the noncovalent assembly of six different homologous subunit types in an array that is strictly defined in terms of both the number and order of each subunit type. Assembly occurs through a mechanism termed “donor-strand exchange (DSE)” in which an N-terminal extension (Nte) of one subunit donates a β-strand to an adjacent subunit, completing its Ig fold. Despite structural determination of the different subunits, the mechanism determining specificity of subunit ordering in pilus assembly remained unclear. Here, we have used noncovalent mass spectrometry to monitor DSE between all 30 possible pairs of P pilus subunits and their Ntes. We demonstrate a striking correlation between the natural order of subunits in pili and their ability to undergo DSE in vitro. The results reveal insights into the molecular mechanism by which subunit ordering during the assembly of this complex is achieved.     

Reappearance of an 11-year-old sequence in an HIV-1 infected patient during treatment interruption

HIV-1 from a patient with multi-drug resistant virus was identified as wild type during treatment interruption. The aim of the study was to describe how the viral population is affected by treatment interruptions and use phylogeny to reconstruct the evolutionary pattern. 15 samples covering 13 y and 2 treatment interruptions were analysed in both pol and env. The wild type virus found in the sample from the second treatment interruption in 2002 had not been present as a dominant population since 1994. Phylogeny showed that the 2002 sample was more closely related to wild type sequences than to other sequences sampled in 2002. This indicated that the wild type virus was caused by recruitment from the viral archives rather than reversion of previously circulating resistant strains. A few weeks after re-initiated treatment, virus showed full resistance, indicating that resistant virus was present as a subpopulation and reselected due to higher fitness in the presence of drugs. Phylogeny of env showed that CCR5 and CXCR4 viruses coexist in the patient. In conclusion, the study showed that at all times during infection, virus is archived in the cells and can be recruited when the surrounding environment changes and the archived virus is more fit.     

Placental passage of benzoic acid, caffeine, and glyphosate in an ex vivo human perfusion system

Ex vivo perfusion of the human term placenta is a method to study placental transfer without extrapolation from animal to human and with no ethical concerns for mother and child. However, ex vivo placenta perfusion has a limited potential within chemical screening and testing as the method is time-consuming. This study was an attempt to construct data needed to develop quantitative structure-activity relationship (QSAR) models that are able to predict placental transfer of new compounds. Placental transfer is a biological activity that statistically may be related to the physiochemical properties of a given group of compounds. Benzoic acid, caffeine, and glyphosate were chosen as model compounds because they are small molecules with large differences in physiochemical properties. Caffeine crossed the placenta by passive diffusion. The initial transfer rate of benzoic acid was more limited in the first part of the perfusion compared to caffeine, but reached the same steady-state level by the end of perfusion. The transfer of glyphosate was restricted throughout perfusion, with a lower permeation rate, and only around 15% glyphosate in maternal circulation crossed to the fetal circulation during the study period.     

A Chinese herbal decoction prepared from Radix Astragali and Radix Angelicae Sinensis induces the expression of erythropoietin in cultured Hep3B cells

Danggui Buxue Tang (DBT), a Chinese medicinal decoction used commonly for treating women's ailments, contains Radix Astragali (RA) and Radix Angelicae Sinensis (RAS). According to Chinese medicinal theory, this decoction is to nourish the blood function; this, however, has not been demonstrated on the molecular level. In order to reveal the hematopoietic effect of this decoction, DBT was applied to cultured Hep3B human hepatocellular carcinoma cells. The treatment of DBT induced mRNA expression of erythropoietin (EPO) in a dose-dependent manner and peaked at approximately 2.5-fold induction. The secreted EPO in cultured Hep3B cells was quantified by ELISA: the treatment of DBT potentiated the effect of hypoxia-induced EPO expression in the cultured cells. In addition, the DBT-induced EPO expression could be abolished by pre-treatment with U0126, a mitogen-activated kinase inhibitor. The current results verified the hematopoietic function of this ancient herbal decoction.