Prostaglandin E and cancer Growth

Summary This paper reviews the evidence linking prostaglandin E (PGE) with the growth of neoplastic tissue. PGE ₂ is present in high concentrations in many natural and experimentally produced cancers. The immunosuppressive effect of some tumors in mice is due at least in part to a prostaglandin mechanism. The growth of these same tumors can be slowed and in some cases the tumor eliminated by administration of PG synthetase inhibitors. It is not yet clear whether the antitumor properties of these PG synthetase inhibitors are due to their releasing the hostimmune system from the chronic prostaglandin-mediated suppression of the tumor, resulting in an effective immune response to the tumor, or whether another mechanism is responsible. In humans overproduction of PGE ₂ by macrophages is partly responsible for the depressed PHA response in patients with Hodgkin's disease.     

Subcutaneous Bortezomib in Multiple Myeloma Patients Induces Similar Therapeutic Response Rates as Intravenous Application But It Does Not Reduce the Incidence of Peripheral Neuropathy

Objective

Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM) patients treated using either intravenous (IV) or subcutaneous (SC) route of administration.

Patients and methods

During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly – 63% or twice weekly – 27%) in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration.

Results

The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥2 was present in 20% vs 18% and PN grade ≥3 was present in 6% vs 4%.

Conclusions

We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.     

Flexibility and structural conservation in a c-KIT G-quadruplex

A quadruplex sequence from the promoter region of the c-KIT gene forms a stable quadruplex, as characterized by crystallographic and NMR methods. Two new crystal structures are reported here, together with molecular dynamics simulation studies on these quadruplex crystal structures and an NMR structure. The new crystal structures, each in a distinct space group and lattice packing arrangement, together with the existing structures, demonstrate that the c-KIT quadruplex fold does not change with differing environments, suggesting that quadruplex topological dynamism is not a general phenomenon. The single and dinucleotide loops in these structures show a high degree of conformational flexibility within the three crystal forms and the NMR ensemble, with no evidence of clustering to particular conformers. This is in accord with the findings of high loop flexibility from the molecular dynamics studies. It is suggested that intramolecular quadruplexes can be grouped into two broad classes (i) those with at least one single-nucleotide loop, often showing singular topologies even though loops are highly flexible, and (ii) with all loops comprising at least two nucleotides, leading to topological dynamism. The loops can have more stable and less dynamic base-stacked secondary structures.     

Can We Distinguish Plant Species that are Rare and Endangered from Other Plants Using Their Biological Traits?

Understanding the factors responsible for species rarity is crucial for effective species conservation. One possible approach to obtaining information about causes of species rarity is to compare rare and common species. We analyzed the biological and ecological traits of critically endangered (CR) plant species of the Czech Republic. We compared the vegetative, generative and ecological traits of CR species with: i) common closely related species (a form of phylogenetic correction), ii) common closely related species sharing the same habitat (i.e., excluding pairs not sharing the same habitat, because many differences in species traits can be caused by adaptation to a specific habitat type) and iii) all plants of the Czech Republic. Information about species traits was mainly obtained from literature and databases. Comparison with common closely related species showed that CR species are smaller, flower for shorter periods, and have higher proportions of self-compatibility and higher terminal velocities. CR species also differ in their mode of dispersion, and their ecology and distribution. Comparison with species from the same habitat gave similar results. Comparison with the whole flora produced slightly different results, with additional differences in pollination mode and seed mass. The results of all three types of comparison suggest that critically endangered species of the Czech Republic are small, competitively inferior species, with some differences in the generative part of their life cycle, and occur mainly in open, unproductive habitats.     

The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms

TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy.     

Bioluminescent bioreporter Pseudomonas putida TVA8 as a detector of water pollution. Operational conditions and selectivity of free cells sensor

Conditions influencing bioluminescence output from Pseudomonas putida TVA8 harboring chromosomal tod-luxCDABE fusion were followed. In complex media, cell growth was not influenced by the presence of toluene at 53 mg/L. Bioluminescence induction was tested in minimal medium. At 15 °C the highest bioluminescence induced with toluene (1.325 mg/L) was reached after 6 h. At 25 °C the bioluminescence maximum was approximately 20% lower but this was reached after 3.5 h, and at temperatures of 7 °C, 28 °C, 30 °C and 34 °C, bioluminescence peaked at ≤60% of the maximum. Time courses of bioluminescence were dependent on cell concentrations. The heights of bioluminescence maxima were proportional to toluene concentration in the range 0–26 mg/L. Twenty-three organic pollutants (10³× diluted saturated solutions) were tested as bioluminescent inducers. The bioluminescence maximum decreased in the order: ethylbenzene > toluene > phenol > benzene > 4-ethyltoluene > 4-fluorotoluene > cumene > isobutylbenzene > styrene > trichloroethylene > o-, p-xylene > cresol > m-xylene > 2-methylnaphthalene > benzylchloride > naphthalene > salicylic acid > hexachlorobenzene > 2-chloronaphthalene > biphenyl > 2-bromonaphthalene > 1,3,5-triethylbenzene. Bioluminescence was also induced with ethanol and methanol and the presence of these alcohols in concentrations of ≤1% increased bioluminescence of toluene. The induction of bioluminescence from samples of wastewater and groundwater contaminated with BTEX (benzene, toluene, ethylbenzene and xylene) from 0.5 to 120 mg/L was demonstrated.     

Sample preparation in separation of the extracellular chitinolytic enzymes of the human intestinal bacterium Clostridium paraputrificum J4 from the culture fluids

Membrane ultrafiltration (UF) was used in sample preparation of the culture fluids of the human intestinal bacterium Clostridium paraputrificum strain J4 containing seven extracellular chitinolytic isoenzymes (38-90 kDa). The subsequent filtration of the bacteria-free supernatants was carried out through Millipore membranes with cut-off 100 and 30 kDa for separation of undigested components of the culture medium and bacterial metabolites with molecular weight higher and lower than that of the target enzymes. The chitinolytic enzymes, which were the minor components in the culture fluids, were concentrated at UF as well. The aim of the research consisted in evaluation of the effect of component composition of bacteria-free supernatants and the chemical nature of membrane active layer on partial fractionation of the chitinolytic enzymes, their recovery in retentates and purification degree. On the basis of the obtained experimental results, the sample preparation procedure of the culture fluids of C. paraputrificum J4 was established to be used further in chromatographic separations of the chitinolytic enzymes.     

Surgery and angiogenesis

Surgery may be regarded as an angiogenesis-inducing condition since it evokes the release of many angiogenic factors. Regarding the mechanistic overlap between tumor-associated neovascularisation and (physiological) angiogenesis in response to injury and hypoxia, surgery may promote the uncontrolled growth of residual dormant tumor cells. With the advent of anti-angiogenic agents, surgeons will be faced with more patients undergoing surgery for primary and secondary tumors under anti-angiogenic treatment. This could present problems with regard to angiogenesis-dependent phenomena such as wound repair, healing of intestinal anastomoses and liver regeneration. In this review we will discuss these matters from a biomedical and clinical point of view.