UNASSIGNED: Exportin 1 (XPO1) inhibitors are being developed as a new agent for anti-cancer therapies. This study aimed to broadly portray the adverse event (AE) profile of selinexor, an XPO1 inhibitor, in actual clinical practice.
UNASSIGNED: Disproportionality analyses were conducted by calculating the information component and reporting odds ratio in VigiBase over different reporting periods. All selinexor-related AEs were classified by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities.
UNASSIGNED: A total of 116,443 AEs were identified in 2,608 patients that received selinexor. Patients with cardiac disorders had a higher propensity for death. Thirteen SOCs and 125 PTs were identified as having a potential connection with selinexor. Notably, 29 suspected signals detected in our study were defined as significant AEs by the European Medicines Agency, including febrile neutropenia, pancytopenia, and acute kidney injury. Attention should be paid to these AEs, despite most toxicities being manageable and reversible.
UNASSIGNED: This study highlights a number of AEs associated with selinexor. Most toxicities are reversible but require careful management. The benefit of selinexor still outweighs the potential risks, indicating XPO1 inhibitors as promising agents.

Short interspersed nuclear elements (SINEs), one type of retrotransposon, are considered to be ideal molecular markers due to their wide distribution in the genome, high copy number, and high polymorphism. Preliminary studies have identified more than 35,000 SINE-retrotransposon insertion polymorphisms (RIPs) in the pig genome. In this study, 18 SINE-RIPs were used to evaluate the genetic variation and population structure of seven native pig populations and two crossbreeds in the Jiangsu Province of China. Two commercial pig breeds (Duroc and Large White) and one Italian native breed (Sicilian Black pig) were selected as the control. The results showed that all 18 SINE-RIPs were polymorphic among these pigs. The Jiangsu native pig populations (Erhualian, Fengjing, Middle Meishan, Mi, Shawutou, Small Meishan, and Huai) were shown to be more polymorphic than the crossbreeds (Sushan and Sujiang) and external breeds (Sicilian Black pig, Large White, and Duroc) based on the expected heterozygosity and polymorphic information content values. Some native pigs, including Small Meishan, Mi, Middle Meishan, and Erhualian, had a higher degree of inbreeding according to the FIS values. Based on the neighbor-joining tree, all of the Jiangsu native pig populations formed one branch, while the three external pig breeds formed the other branches, with the two crossbreeds containing more than 50% external pig ancestry. The Huai pigs were independent of the other Jiangsu native pigs but shared a common ancestor with Sujiang and Mi. The results provide a new perspective on the population structure of these native pig breeds and will assist with the conservation and utilization of Chinese native pigs.

The diversity of livestock coat color results from human positive selection and represents an indispensable part of breed identity. As an important biodiversity resource, pigs have many special characteristics, including the most visualized feature, coat color, and excellent adaptation, and the coat color represents an important phenotypic characteristic of the pig breed. Exploring the genetic mechanisms of phenotypic characteristics and the melanocortin system is of considerable interest in domestic animals because their energy metabolism and pigmentation have been under strong selection. In this study, 20 genes related to coat color in mammals were selected, and the structural variations (SVs) in these genic regions were identified by sequence alignment across 17 assembled pig genomes, from representing different types of pigs (miniature, lean, and fat type). A total of 167 large structural variations (>50 bp) of coat-color genes, which overlap with retrotransposon insertions (>50 bp), were obtained and designated as putative RIPs. Finally, 42 RIPs were confirmed by PCR detection. Additionally, eleven RIP sites were further evaluated for their genotypic distributions by PCR in more individuals of eleven domesticated breeds representing different coat color groups. Differential distributions of these RIPs were observed across populations, and some RIPs may be associated with breed differences.

The genetic diversity of the GH/IGF axis genes and their association with the variation of gene expression and phenotypic traits, principally represented by SNPs, have been extensively reported. Nevertheless, the impact of retrotransposon insertion polymorphisms (RIPs) on the GH/IGF axis gene activity has not been reported. In the present study, bioinformatic prediction and PCR verification were performed to screen RIPs in four GH/IGF axis genes (GH, GHR, IGF1 and IGF1R). In total, five RIPs, including one SINE RIP in intron 3 of IGF1, one L1 RIP in intron 7 of GHR, and three SINE RIPs in intron 1, intron 5 and intron 9 of GHR, were confirmed by PCR, displaying polymorphisms in diverse breeds. Dual luciferase reporter assay revealed that the SINE insertion in intron 1 of GHR significantly repressed the GHR promoter activity in PK15, Hela, C2C12 and 3T3-L1 cells. Furthermore, qPCR results confirmed that this SINE insertion was associated with a decreased expression of GHR in the leg muscle and longissimus dorsi, indicating that it may act as a repressor involved in the regulation of GHR expression. In summary, our data revealed that RIPs contribute to the genetic variation of GH/IGF axis genes, whereby one SINE RIP in the intron 1 of GHR may decrease the expression of GHR by acting as a repressor.

BACKGROUND: Molecular markers based on retrotransposon insertion polymorphisms (RIPs) have been developed and are widely used in plants and animals. Short interspersed nuclear elements (SINEs) exert wide impacts on gene activity and even on phenotypes. However, SINE RIP profiles in livestock remain largely unknown, and not be revealed in pigs.
RESULTS: Our data revealed that SINEA1 displayed the most polymorphic insertions (22.5 % intragenic and 26.5 % intergenic), followed by SINEA2 (10.5 % intragenic and 9 % intergenic) and SINEA3 (12.5 % intragenic and 5.0 % intergenic). We developed a genome-wide SINE RIP mining protocol and obtained a large number of SINE RIPs (36,284), with over 80 % accuracy and an even distribution in chromosomes (14.5/Mb), and 74.34 % of SINE RIPs generated by SINEA1 element. Over 65 % of pig SINE RIPs overlap with genes, most of them (> 95 %) are in introns. Overall, about one forth (23.09 %) of the total genes contain SINE RIPs. Significant biases of SINE RIPs in the transcripts of protein coding genes were observed. Nearly half of the RIPs are common in these pig breeds. Sixteen SINE RIPs were applied for population genetic analysis in 23 pig breeds, the phylogeny tree and cluster analysis were generally consistent with the geographical distributions of native pig breeds in China.
CONCLUSIONS: Our analysis revealed that SINEA1-3 elements, particularly SINEA1, are high polymorphic across different pig breeds, and generate large-scale structural variations in the pig genomes. And over 35,000 SINE RIP markers were obtained. These data indicate that young SINE elements play important roles in creating new genetic variations and shaping the evolution of pig genome, and also provide strong evidences to support the great potential of SINE RIPs as genetic markers, which can be used for population genetic analysis and quantitative trait locus (QTL) mapping in pig.

RIPs have been developed as effective genetic markers and popularly applied for genetic analysis in plants, but few reports are available for domestic animals. Here, we established 30 new molecular markers based on the SINE RIPs, and applied them for population genetic analysis in seven Chinese miniature pigs. The data revealed that the closed herd (BM-clo), inbreeding herd (BM-inb) of Bama miniature pigs were distinctly different from the BM-cov herds in the conservation farm, and other miniature pigs (Wuzhishan, Congjiang Xiang, Tibetan, and Mingguang small ear). These later five miniature pig breeds can further be classified into two clades based on a phylogenetic tree: one included BM-cov and Wuzhishan, the other included Congjiang Xiang, Tibetan, and Mingguang small ear, which was well-supported by structure analysis. The polymorphic information contents estimated by using SINE RIPs are lower than the predictions based on microsatellites. Overall, the genetic distances and breed-relationships between these populations revealed by 30 SINE RIPs generally agree with their evolutions and geographic distributions. We demonstrated the potential of SINE RIPs as new genetic markers for genetic monitoring and population structure analysis in pigs, which can even be extended to other livestock animals.

Short interspersed nuclear elements (SINEs) are nonautonomous retrotransposons that occupy approximately 13% of the human genome. They are transcribed by RNA polymerase III and can be retrotranscribed and inserted back into the genome with the help of other autonomous retroelements. Because they are preferentially located close to or within gene-rich regions, they can regulate gene expression by various mechanisms that act at both the DNA and the RNA levels. In this review, we summarize recent findings on the involvement of SINEs in different types of gene regulation and discuss the potential regulatory functions of SINEs that are in close proximity to genes, Pol III-transcribed SINE RNAs, and embedded SINE sequences within Pol II-transcribed genes in the human genome. These discoveries illustrate how the human genome has exapted some SINEs into functional regulatory elements.

Repetitive elements are abundantly distributed in mammalian genomes. Here, we reveal a striking association between repeat subtypes and gene function. SINE, L1, and low-complexity repeats demarcate distinct functional categories of genes and may dictate the time and level of gene expression by providing binding sites for different regulatory proteins. Importantly, imaging and sequencing analysis show that L1 repeats sequester a large set of genes with specialized functions in nucleolus- and lamina-associated inactive domains that are depleted of SINE repeats. In addition, L1 transcripts bind extensively to its DNA in embryonic stem cells (ESCs). Depletion of L1 RNA in ESCs leads to relocation of L1-enriched chromosomal segments from inactive domains to the nuclear interior and de-repression of L1-associated genes. These results demonstrate a role of L1 DNA and RNA in gene silencing and suggest a general theme of genomic repeats in orchestrating the function, regulation, and expression of their host genes.

Horizontal transfer of genetic materials between virus and host has been frequently identified. Three rice planthoppers, Laodelphax striatellus, Nilaparvata lugens, and Sogatella furcifera, are agriculturally important insects because they are destructive rice pests and also the vector of a number of phytopathogenic viruses. In this study, we discovered that a small region (∼300 nucleotides [nt]) of the genome of invertebrate iridescent virus 6 (IIV-6; genus Iridovirus, family Iridoviridae), a giant DNA virus that infects invertebrates but is not known to infect planthoppers, is highly homologous to the sequences present in high copy numbers in these three planthopper genomes. These sequences are related to the short interspersed nuclear elements (SINEs), a class of non-long terminal repeat (LTR) retrotransposons (retroposons), suggesting a horizontal transfer event of a transposable element from the rice planthopper genome to the IIV-6 genome. In addition, a number of planthopper transcripts mapped to these rice planthopper SINE-like sequences (RPSlSs) were identified and appear to be transcriptionally regulated along the different developmental stages of planthoppers. Small RNAs derived from these RPSlSs are predominantly 26 to 28 nt long, which is a typical characteristic of PIWI-interacting RNAs. Phylogenetic analysis suggests that IIV-6 acquires a SINE-like retrotransposon from S. furcifera after the evolutionary divergence of the three rice planthoppers. This study provides further examples of the horizontal transfer of an insect transposon to virus and suggests the association of rice planthoppers with iridoviruses in the past or present.IMPORTANCE This study provides an example of the horizontal transfer event from a rice planthopper genome to an IIV-6 genome. A small region of the IIV-6 genome (∼300 nt) is highly homologous to the sequences presented in high copy numbers of three rice planthopper genomes that are related to the SINEs, a class of retroposons. The expression of these planthopper SINE-like sequences was confirmed, and corresponding Piwi-interacting RNA-like small RNAs were identified and comprehensively characterized. Phylogenetic analysis suggests that the giant invertebrate iridovirus IIV-6 obtains this SINE-related sequence from Sogatella furcifera through a horizontal transfer event in the past. To the best of our knowledge, this is the first report of a horizontal transfer event between a planthopper and a giant DNA virus and also is the first evidence for the eukaryotic origin of genetic material in iridoviruses.

The aim of the study was to investigate the SINE polymorphism in Xiang, Kele, Qianbei black, Jiangkouluobo, Large White, and Duroc pig breeds. The PCR based detection method was conducted to identify the short interspersed nuclear element (SINE) polymorphism in the PDIA4 gene. There were greater frequencies of the SINE-/- genotypes in Xiang pigs (55.9%) as compared with other pig breed groups. There was an association between this 275 bp SINE polymorphism and litter size (P = 0.003). The homozygous SINE+/+ genotype of the PDIA4 gene had a 1.45-piglets larger litter sizes compared to those with the homozygous SINE-/- genotype. Furthermore, there were assessments of mRNA and protein abundances as a result of PDIA4 gene expression in the ovaries of Xiang pigs for the three different SINE genotypes, and the results indicated that relative abundances of PDIA4 mRNA and protein was greater for the SINE-/- and SINE-/+ genotypes compared with the SINE+/+ genotype (P < 0.05). These findings suggested that the 275 bp SINE polymorphism might change the expression of the PDIA4 gene and could be used as a candidate DNA marker for the selection for litter size in Xiang pigs.