Multitargeted therapies for multiple myeloma

Multiple myeloma (MM) comprises 1% of all malignancies and 10% of all hematological malignancies. MM is a malignancy of plasma cells in the bone marrow where complex and dynamic interactions with the bone marrow microenvironment lead to tumor progression, skeletal destruction and angiogenesis. Despite the discovery of several novel treatments against MM, including the proteasome inhibitor bortezomib, it is considered to be an incurable disease with an average 4–5 years overall survival.     

Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B- and Hirschsprung disease-associated missense mutations of the RET gene

Missense mutations of the RET gene have been identified in both multiple endocrine neoplasia (MEN) type 2A/B and Hirschsprung disease (HSCR: congenital absence of the enteric nervous system, ENS). Current consensus holds that MEN2A/B and HSCR are caused by activating and inactivating RET mutations, respectively. However, the biological significance of RET missense mutations in vivo has not been fully elucidated. In the present study, we introduced one MEN2B-associated (M918T) and two HSCR-associated (N394K and Y791F) RET missense mutations into the corresponding regions of the mouse Ret gene by genome editing (Ret^M919T, Ret^N396K and Ret^Y792F) and performed histological examinations of Ret-expressing tissues to understand the pathogenetic impact of each mutant in vivo. Ret^M919T/+ mice displayed MEN2B-related phenotypes, including C-cell hyperplasia and abnormal enlargement of the primary sympathetic ganglia. Similar sympathetic phenotype was observed in Ret^M919T/- mice, demonstrating a strong pathogenetic effect of the Ret M918T by a single-allele expression. In contrast, no abnormality was found in the ENS of mice harboring the Ret N394K or Y791F mutation. Most surprisingly, single-allele expression of RET N394K or Y791F was sufficient for normal ENS development, indicating that these RET mutants exert largely physiological function in vivo. This study reveals contrasting pathogenetic effects between MEN2B- and HSCR-associated RET missense mutations, and suggests that some of HSCR-associated RET missense mutations are by themselves neither inactivating nor pathogenetic and require involvement of other gene mutations for disease expressivity.     

Wolbachia prevalence patterns: horizontal transmission,recombination, and multiple infections in chestnut gall wasp-parasitoid communities

The Oriental chestnut gall wasp, Dryocosmus kuriphilus Yasumatsu (Hymenoptera: Cynipidae), is a global invasive pest that causes serious damage to almost all chestnut species belonging to the Castanea genus (Fagaceae). Dryocosmus zhuili Liu et Zhu is a recently described sibling species of D. kuriphilus, which induces galls on Castanea henryi (Skan) Rehd. et Wils. There are many indigenous parasitoid species in China which play an important role in the natural regulation of their population dynamics. Wolbachia is a maternally inherited α-proteobacterium widely found in arthropods. This study screened for the presence of Wolbachia in the two chestnut gall wasps and in six parasitoid species from 12 populations, to investigate the prevalence patterns of Wolbachia in the chestnut gall wasp-parasitoid communities. We found that D. zhuili and four parasitoid species were infected with Wolbachia; among them, all individuals of the two populations of Megastigmus sp. had multiple Wolbachia infections. By using multilocus sequence types to characterize bacterial strains, three new sequence types were identified. The Wolbachia strains infecting D. zhuili (ST-507), Torymus sinensis Kamijo (ST-508), and Sycophila variegata (Curtis) (ST-508) belonged to supergroup A, whereas the Wolbachia strain infecting Megastigmus nipponicus Kamijo (ST-503) belonged to supergroup B. Our results also suggested that horizontal transmission of Wolbachia occurs between chestnut gall wasps and their parasitoids. Moreover, multiple Wolbachia infections of Megastigmus sp. may be due to gene recombination and horizontal transmission.     

The interplay between local and landscape scales on the density of pond-dwelling anurans in subtropical grasslands

We investigated the role of local and landscape environmental variables on anurans density classified as habitat specialists and generalists in grassland landscapes, known as South Brazilian grasslands (SBG). In this region, we surveyed 187 ponds distributed over 40 landscape sampling units. For each pond, 31 local environmental variables were measured. Each landscape sampling unit was embedded within a larger regional sampling unit with different landscape properties. For each landscape and regional sampling units, 16 landscape metrics were extracted from a land cover and use map. We recorded 35 species, eleven of which are specialists in the SBG. The specialists were affected by 11 local and 2 landscape environmental variables, while generalists were affected by 14 local and one landscape environmental variable. Thus, specialists and generalists presented different relationships with local and landscape variables, but in general local variables had a greater influence on the density of anurans than the landscape variables. However, the landscape indirectly influenced local variables because higher quality ponds were in landscapes with higher percentages of natural habitat. In conclusion, reproductive sites with higher local quality and located within landscapes with higher percentages of natural grasslands are essential to conserve anurans in this habitat. Effective conservation of such sites would benefit from further studies that assess effects of land use and biotic integrity of ponds, which can help to determine (a) the relative effects of local habitat quality of ponds and (b) the effectiveness of protecting ponds and their local surroundings for anuran conservation in SBG. Abstract in Portuguese is available with online material.     

Roles of noncoding RNAs in drug resistance in multiple myeloma

Despite the administration of new effective drugs in recent years, relapse and drug resistance are still the main obstacles in multiple myeloma (MM) treatment, making MM an incurable disease. To overcome drug resistance in MM, it is critical to understand the underlying mechanisms of malfunctioning gene expression and develop novel targeted therapies. During the past few decades, with the discovery and characterization of noncoding RNAs (ncRNAs), the landscape of dysregulated ncRNAs of cancers as well as their biological and pathobiological functions in tumorigenesis and drug resistance have been recognized. Studies about ncRNAs improved the understanding of variations of drug response among individuals at a level distinguished from genetic polymorphism, and provided with new orientations for targeted therapies. In this review, we will summarize the emerging impact and underlying molecular mechanisms of the most relevant classes of ncRNAs in drug resistance of MM, and discuss the potential as well as strategies of treating ncRNAs as therapeutic targets.     

Locating QTLs controlling several adult root traits in an elite Chinese hybrid rice

This study aimed to elucidate the genetics of the adult root system in elite Chinese hybrid rice. Several adult root traits in a recombinant inbred line (RIL) population of Xieyou 9308 and two backcross F₁ (BCF₁) populations derived from the RILs were phenotyped under hydroponic culture at heading stage for quantitative trait locus (QTL) mapping and other statistical analysis. There a total of eight QTLs detected for the root traits. Among of them, a pleiotropic QTL was repeatedly flanked by RM180 and RM5436 on the short arm of chromosome 7 for multiple traits across RILs and its BCF₁ populations, accounting for 6.88% to 25.26% of the phenotypic variances. Only additive/dominant QTLs were detected for the root traits. These results can serve as a foundation for facilitating future cloning and molecular breeding.     

Different coexpressions of arthritis-relevant genes between different body organs and different brain regions in the normal mouse population

Structural changes in different parts of the brain in rheumatoid arthritis (RA) patients have been reported. RA is not regarded as a brain disease. Body organs such as spleen and lung produce RA-relevant genes. We hypothesized that the structural changes in the brain are caused by changes of gene expression in body organs. Changes in different parts of the brain may be affected by altered gene expressions in different body organs. This study explored whether an association between gene expressions of an organ or a body part varies in different brain structures. By examining the association of the 10 most altered genes from a mouse model of spontaneous arthritis in a normal mouse population, we found two groups of gene expression patterns between five brain structures and spleen. The correlation patterns between the prefrontal cortex, nucleus accumbens, and spleen were similar, while the associations between the other three parts of the brain and spleen showed a different pattern. Among overall patterns of the associations between body organs and brain structures, spleen and lung had a similar pattern, and patterns for kidney and liver were similar. Analysis of the five additional known arthritis-relevant genes produced similar results. Analysis of 10 nonrelevant-arthritis genes did not result in a strong association of gene expression or clearly segregated patterns. Our data suggest that abnormal gene expressions in different diseased body organs may influence structural changes in different brain parts.     

Concepts and analysis of mass extinction with the late Ordovician event as an example

Twelve groups of fossils, including graptolites, brachiopods, nautiloids, trilobites, corals, crinoids, bryozoans, conodonts, ostracods, gastropods, chitinozoans, and acritarchs expired in different but substantial magnitude and global extent during the late Caradoc to latest Ashgill. It indicates a multiple‐episodic mass extinction containing the possible Prologue (late Caradoc), Climax episode (Rawtheyan) and Epilogue (late Hirnantian). The main causes of this mass extinction are recognized as a global sea‐level lowering in the climax and remarkable rapid rise at the final, and global cooling. The Chinese data, especially from the South China Paleoplate, are evaluated first. They are significant for explaining this global bioevent.     

π–π Stacking mediated drug–drug interactions in human CYP2E1

Because of having many low molecular mass substrates, CYP2E1 is of particular interests to the pharmaceutical industry. Many evidences showed that this enzyme can adopt multiple substrates to significantly reduce the oxidation rate of the substrates. The detailed mechanism for this observation is still unclear. In the current study, we employed GPU‐accelerated molecular dynamics simulations to study the multiple‐binding mode of human CYP2E1, with an aim of offering a mechanistic explanation for the unexplained multiple‐substrate binding. Our results showed that Thr303 and Phe478 were key factors for the substrate recognition and multiple‐substrate binding. The former can form a significant hydrogen bond to recognize and position the substrate in the productive binding orientation in the active site. The latter acted as a mediator for the substrate communications via π–π stacking interactions. In the multiple‐binding mode, the aforementioned π–π stacking interactions formed by the aromatic rings of both substrates and Phe478 drove the first substrate far away from the catalytic center, orienting in an additional binding position and going against the substrate metabolism. All these findings could give atomic insights into the detailed mechanism for the multiple‐substrate binding in human CYP2E1, providing useful information for the drug metabolism mechanism and personalized use of clinical drugs. Proteins 2013; © 2012 Wiley Periodicals, Inc.