Identification of the Key Regulatory Genes Involved in Elaborate Petal Development and Specialized Character Formation in Nigella damascena (Ranunculaceae).

Petals can be simple or elaborate, depending on whether they have lobes, teeth, fringes, or appendages along their margins, or possess spurs, scales, or other types of modifications on their adaxial/abaxial side, or both. Elaborate petals have been recorded in 23 orders of angiosperms and are generally believed to have played key roles in the adaptive evolution of corresponding lineages. The mechanisms underlying the formation of elaborate petals, however, are largely unclear. Here, by performing extensive transcriptomic and functional studies on Nigella damascena (Ranunculaceae), we explore the mechanisms underlying elaborate petal development and specialized character formation. In addition to the identification of genes and programs that are specifically/preferentially expressed in petals, we found genes and programs that are required for elaborate rather than simple petal development. By correlating the changes in gene expression with those in petal development, we identified 30 genes that are responsible for the marginal/ventral elaboration of petals and the initiation of several highly specialized morphological characters (e.g., pseudonectaries, long hairs, and short trichomes). Expression and functional analyses further confirmed that a class I homeodomain-leucine zipper family transcription factor gene, Nigella damascena LATE MERISTEM IDENTITY1 (NidaLMI1), plays important roles in the development of short trichomes and bifurcation of the lower lip. Our results not only provide the first portrait of elaborate petal development but also pave the way to understanding the mechanisms underlying lateral organ diversification in plants.

Identification of the target genes of AqAPETALA3-3 (AqAP3-3) in Aquilegia coerulea (Ranunculaceae) helps understand the molecular bases of the conserved and nonconserved features of petals.

Identification and comparison of the conserved and variable downstream genes of floral organ identity regulators are critical to understanding the mechanisms underlying the commonalities and peculiarities of floral organs. Yet, because of the lack of studies in nonmodel species, a general picture of the regulatory evolution between floral organ identity genes and their targets is still lacking. Here, by conducting extensive chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), electrophoretic mobility shift assay and bioinformatic analyses, we identify and predict the target genes of a petal identity gene, AqAPETALA3-3 (AqAP3-3), in Aquilegia coerulea (Ranunculaceae) and compare them with those of its counterpart in Arabidopsis thaliana, AP3. In total, 7049 direct target genes are identified for AqAP3-3, of which 2394 are highly confident and 1085 are shared with AP3. Gene Ontology enrichment analyses further indicate that conserved targets are largely involved in the formation of identity-related features, whereas nonconserved targets are mostly required for the formation of species-specific features. These results not only help understand the molecular bases of the conserved and nonconserved features of petals, but also pave the way to studying the regulatory evolution between floral organ identity genes and their targets.

Chloroplast genomic data provide new and robust insights into the phylogeny and evolution of the Ranunculaceae.

The family Ranunculaceae, a member of early-diverging eudicots that is increasingly being used as a model for the study of plant developmental evolution, has been the focus of systematic studies for centuries. Recent studies showed that the family can be divided into 14 tribes, with Glaucideae, Hydrastideae, and Coptideae being the successive basal-most lineages. The relationships among the remaining 11 tribes, however, remain controversial, so that a clear picture of character evolution within the family is still lacking. In this study, by sequencing, assembling and analyzing the chloroplast (cp) genomes of 35 species representing 31 genera of the 14 tribes, we resolved the relationships among the tribes and genera of the Ranunculaceae and clarified several long-standing controversies. We found that many of the characters that were once widely used for taxonomic and systematic considerations were actually results of parallel, convergent or even reversal evolution, suggestive of unreliability. We also found that the family has likely experienced two waves of radiative evolution, through which most of the extant tribes and genera were generated. Notably, both waves of radiation were correlated with the increase in the temperature of the earth, suggesting that global warming may have been the driving force of the radiation events. Based on these observations, we hypothesize that global warming and the associated decrease in the type and number of animal pollinators may have been the main reason why taxa with highly elaborate petals as well as those without petal were generated during each of the two waves of radiation.

Meta-analysis of adjunctive dexamethasone to improve clinical outcome of bacterial meningitis in children.

BACKGROUND: The current recommended therapies for bacterial meningitis are effective antimicrobial agents and the implementation of childhood vaccination programs. However, the role of adjunctive dexamethasone therapy in bacterial meningitis remains controversial. METHODS: Using meta-analysis, this study aims to investigate the efficacy of adjunctive dexamethasone therapy in bacterial meningitis by comparing it with antibiotic therapy. Documents of randomized controlled trials (RCT) related to the treatment of bacterial meningitis in children with dexamethasone published since the establishment of the databases to December in 2016 were retrieved from the databases of Cochrane Library, Pubmed, MEDLINE, EMBASE, Chinese BioMedical Literature Database, and China National Knowledge Infrastructure. The references in RCT were retrieved by hands at the same time. Full texts of screened documents were searched and given qualitative review, and then, all RCT included were analyzed statistically by using Review Manger 5.3 software. RESULTS: The search yielded 15 studies (2409 children cases), among which 4 fall in grade A and 11 were grade B. The results of meta-analysis have shown that patients who received dexamethasone have significantly lower risks in incidence of hearing loss (OR = 0.68, 95%CI 0.53-0.89, P = 0.004) and severe neurological sequelae (OR = 0.59, 95%CI 0.37-0.95, P = 0.03), but the follow-up mortality is hardly effected (OR = 0.86, 95%CI 0.67-1.10, P = 0.23). CONCLUSIONS: Evidence has proven that the adjunctive administration of dexamethasone is conducive to treating children with bacterial meningitis to a certain extent, to decreasing the possibility of hearing loss and severe neurological sequelae, but has no significant effect on the follow-up mortality.

Correction to: Meta-analysis of adjunctive dexamethasone to improve clinical outcome of bacterial meningitis in children.

The original version of this article unfortunately contained an error.

Human coding RNA editing is generally nonadaptive.

Impairment of RNA editing at a handful of coding sites causes severe disorders, prompting the view that coding RNA editing is highly advantageous. Recent genomic studies have expanded the list of human coding RNA editing sites by more than 100 times, raising the question of how common advantageous RNA editing is. Analyzing 1,783 human coding A-to-G editing sites, we show that both the frequency and level of RNA editing decrease as the importance of a site or gene increases; that during evolution, edited As are more likely than unedited As to be replaced with Gs but not with Ts or Cs; and that among nonsynonymously edited As, those that are evolutionarily least conserved exhibit the highest editing levels. These and other observations reveal the overall nonadaptive nature of coding RNA editing, despite the presence of a few sites in which editing is clearly beneficial. We propose that most observed coding RNA editing results from tolerable promiscuous targeting by RNA editing enzymes, the original physiological functions of which remain elusive.

In search of beneficial coding RNA editing.

RNA editing is a posttranscriptional modification that can lead to a change in the encoded protein sequence of a gene. Although a few cases of mammalian coding RNA editing are known to be functionally important, the vast majority of over 2,000 A-to-I editing sites that have been identified from the coding regions of the human genome are likely nonadaptive, representing tolerable promiscuous targeting of editing enzymes. Finding the potentially tiny fraction of beneficial editing sites from the sea of mostly nearly neutral editing is a difficult but important task. Here, we propose and provide evidence that evolutionarily conserved or "hardwired" residues that experience high-level nonsynonymous RNA editing in a species are enriched with beneficial editing. This simple approach allows the prediction of sites where RNA editing is functionally important. We suggest that priority be given to these candidates in future characterizations of the functional and fitness consequences of RNA editing.

MicroRNA-410-5p as a potential serum biomarker for the diagnosis of prostate cancer.

BACKGROUND: Prostate cancer (PCa) remains to be a diagnostic challenge due to its variable presentation and the lack of reliable diagnosis tool. MicroRNAs (miRNAs) regulate gene in extensive range of pathophysiologic processes. Plasma miRNAs are ideal biomarkers in heart failure, diabetes and other disease. However, using circulating miRNAs as biomarkers for the diagnosis of PCa is still unknown. METHODS: 149 PCa patients, 57 healthy controls, and 121 non-cancer patients (benign prostatic hyperplasia and other urinary diseases) were enrolled in this study. The reverse transcription of miRNA and SYBR-Green-based double standards curve miRNA quantitative polymerase chain reactions (qPCR) were used to evaluate the dysregulated miR-410-5p. Receiver operator characteristic (ROC) curve analysis was used to evaluate the diagnostic accuracy of miR-410-5p identified as the alternative biomarker. RESULTS: Circulating miRNA-410-5p (miR-410-5p) level was significantly higher in the PCa patients than in healthy controls or non-cancer patients. ROC curve analysis showed that plasma miR-410-5p was a specific diagnostic biomarker of PCa with an area under curve(AUC) of 0.8097 (95 % confidence interval, 0.7371-0.8823; P < 0.001). CONCLUSIONS: The serum miR-410-5p level is a potential biomarker for the diagnosis of PCa.

Divergence of duplicate genes in exon-intron structure.

Gene duplication plays key roles in organismal evolution. Duplicate genes, if they survive, tend to diverge in regulatory and coding regions. Divergences in coding regions, especially those that can change the function of the gene, can be caused by amino acid-altering substitutions and/or alterations in exon-intron structure. Much has been learned about the mode, tempo, and consequences of nucleotide substitutions, yet relatively little is known about structural divergences. In this study, by analyzing 612 pairs of sibling paralogs from seven representative gene families and 300 pairs of one-to-one orthologs from different species, we investigated the occurrence and relative importance of structural divergences during the evolution of duplicate and nonduplicate genes. We found that structural divergences have been very prevalent in duplicate genes and, in many cases, have led to the generation of functionally distinct paralogs. Comparisons of the genomic sequences of these genes further indicated that the differences in exon-intron structure were actually accomplished by three main types of mechanisms (exon/intron gain/loss, exonization/pseudoexonization, and insertion/deletion), each of which contributed differently to structural divergence. Like nucleotide substitutions, insertion/deletion and exonization/pseudoexonization occurred more or less randomly, with the number of observable mutational events per gene pair being largely proportional to evolutionary time. Notably, however, compared with paralogs with similar evolutionary times, orthologs have accumulated significantly fewer structural changes, whereas the amounts of amino acid replacements accumulated did not show clear differences. This finding suggests that structural divergences have played a more important role during the evolution of duplicate than nonduplicate genes.

Combined analysis of metabolomics and 16S rRNA sequencing for ankylosing spondylitis patients before and after secukinumab therapy.

OBJECTIVE: Alterations in gut microbiota have been implicated in the pathogenesis of ankylosing spondylitis (AS), but the underlying mechanisms remain elusive. This study aims to investigate changes in gut microbiota and metabolites in individuals with AS before and after treatment with secukinumab, to identify the biological characteristics specific to AS patients and investigate the potential biomarkers, for optimizing therapeutic strategies more effectively. METHODS: Fecal microbiome data were collected from 30 AS patients before and after secukinumab therapy and compared with data from 40 healthy controls (HC). Additionally, we analyzed the metabolic profile of both groups from plasma. RESULTS: Findings indicated that the treatment-induced changes in the composition of several crucial bacterial groups, including Megamonas, Prevotella_9, Faecalibacterium, Roseburia, Bacteroides, and Agathobacter. Post-treatment, these groups exhibited a distribution more akin to that of the healthy populations compared with their pretreatment status. We identified three gut microbial taxa, namely Prevotellaceae_bacterium_Marseille_P2831, Prevotella_buccae, and Elusimicrobiota, as potential biomarkers for diagnosing individuals at a higher risk of developing AS and assessing disease outcomes. Plasma metabolomics analysis revealed 479 distinct metabolites and highlighted three disrupted metabolic pathways. Integration of microbiome and metabolomics datasets demonstrated a significant degree of correlation, underscoring the impact of the microbiome on metabolic activity. CONCLUSION: Secukinumab can restore the balance of the gut microbiome and metabolites in AS patients, rendering them more similar to those found in the healthy population. The analysis of microbiome and metabolomics data have unveiled some candidate biomarkers capable of evaluating treatment efficacy.

Genomic data and ecological niche modeling reveal an unusually slow rate of molecular evolution in the Cretaceous Eupteleaceae.

Living fossils are evidence of long-term sustained ecological success. However, whether living fossils have little molecular changes remains poorly known, particularly in plants. Here, we have introduced a novel method that integrates phylogenomic, comparative genomic, and ecological niche modeling analyses to investigate the rate of molecular evolution of Eupteleaceae, a Cretaceous relict angiosperm family endemic to East Asia. We assembled a high-quality chromosome-level nuclear genome, and the chloroplast and mitochondrial genomes of a member of Eupteleaceae (Euptelea pleiosperma). Our results show that Eupteleaceae is most basal in Ranunculales, the earliest-diverging order in eudicots, and shares an ancient whole-genome duplication event with the other Ranunculales. We document that Eupteleaceae has the slowest rate of molecular changes in the observed angiosperms. The unusually low rate of molecular evolution of Eupteleaceae across all three independent inherited genomes and genes within each of the three genomes is in association with its conserved genome architecture, ancestral woody habit, and conserved niche requirements. Our findings reveal the evolution and adaptation of living fossil plants through large-scale environmental change and also provide new insights into early eudicot diversification.

Evolution of F-box genes in plants: different modes of sequence divergence and their relationships with functional diversification.

F-box proteins are substrate-recognition components of the Skp1-Rbx1-Cul1-F-box protein (SCF) ubiquitin ligases. In plants, F-box genes form one of the largest multigene superfamilies and control many important biological functions. However, it is unclear how and why plants have acquired a large number of F-box genes. Here we identified 692, 337, and 779 F-box genes in Arabidopsis, poplar and rice, respectively, and studied their phylogenetic relationships and evolutionary patterns. We found that the plant F-box superfamily can be divided into 42 families, each of which has a distinct domain organization. We also estimated the number of ancestral genes for each family and identified highly conservative versus divergent families. In conservative families, there has been little or no change in the number of genes since the divergence between eudicots and monocots approximately 145 million years ago. In divergent families, however, the numbers have increased dramatically during the same period. In two cases, the numbers of genes in extant species are >100 times greater than that in the most recent common ancestor (MRCA) of the three species. Proteins encoded by highly conservative genes always have the same domain organization, suggesting that they interact with the same or similar substrates. In contrast, proteins of rapidly duplicating genes sometimes have quite different domain structures, mainly caused by unusually frequent shifts of exon-intron boundaries and/or frameshift mutations. Our results indicate that different F-box families, or different clusters of the same family, have experienced dramatically different modes of sequence divergence, apparently having resulted in adaptive changes in function.

Silencing of long noncoding RNA TUG1 inhibits viability and promotes apoptosis of acute myeloid leukemia cells by targeting microRNA-221-3p/KIT axis.

OBJECTIVE: Acute myeloid leukemia (AML) is a hematological malignancy. This study was attempted to uncover the effects of long noncoding RNA taurine-upregulated gene1 (TUG1) on the viability and apoptosis of AML cells. METHODS: QRT-PCR was implemented to examine the expression of TUG1, miR-221-3p and KIT in AML. The correlation between TUG1 and clinicopathological features of AML patients was evaluated. The effect of TUG1 on AML cells were studied by RNA interference approach. AML cells were transfected with miR-221-3p mimic and miR-221-3p inhibitor, respectively. Then the viability and apoptosis of AML cells were examined by MTT and flow cytometry assay, respectively. Additionally, dual-luciferase reporter assay was used to confirm the interactions among TUG1, miR-221-3p and KIT. Western blot was applied to analyze protein expression of KIT. RESULTS: The expression of TUG1 and KIT was up-regulated in AML, but miR-221-3p was down-regulated. TUG1 expression had obviously correlation with World Health Organization (WHO) grade in AML patients. The functional experiment stated that TUG1 silencing suppressed the viability and accelerated the apoptosis of AML cells. Moreover, the mechanical experiment demonstrated that TUG1 and KIT were both targeted by miR-221-3p with the complementary binding sites at 3'UTR. Up-regulation of miR-221-3p inhibited the protein expression of KIT. Furthermore, in the feedback experiment, miR-221-3p inhibition or KIT overexpression reversed the repression of tumor behavior induced by TUG1 silencing. CONCLUSIONS: TUG1 silencing retarded viability and promoted apoptosis of AML cells via regulating miR-221-3p/KIT axis, providing a potential therapeutic target for AML.

A chromosome-scale reference genome of Aquilegia oxysepala var. kansuensis.

The genus Aquilegia (Ranunculaceae) has been cultivated as ornamental and medicinal plants for centuries. With petal spurs of strikingly diverse size and shape, Aquilegia has also been recognized as an excellent system for evolutionary studies. Pollinator-mediated selection for longer spurs is believed to have shaped the evolution of this genus, especially the North American taxa. Recently, however, an opposite evolutionary trend was reported in an Asian lineage, where multiple origins of mini- or even nonspurred morphs have occurred. Interesting as it is, the lack of genomic resources has limited our ability to decipher the molecular and evolutionary mechanisms underlying spur reduction in this special lineage. Using long-read sequencing (PacBio Sequel), in combination with optical maps (BioNano DLS) and Hi-C, we assembled a high-quality reference genome of A. oxysepala var. kansuensis, a sister species to the nonspurred taxon. The final assembly is approximately 293.2 Mb, 94.6% (277.4 Mb) of which has been anchored to 7 pseudochromosomes. A total of 25,571 protein-coding genes were predicted, with 97.2% being functionally annotated. When comparing this genome with that of A. coerulea, we detected a large rearrangement between Chr1 and Chr4, which might have caused the Chr4 of A. oxysepala var. kansuensis to partly deviate from the "decaying" path that was taken before the split of Aquilegia and Semiaquilegia. This high-quality reference genome is fundamental to further investigations on the development and evolution of petal spurs and provides a strong foundation for the breeding of new horticultural Aquilegia cultivars.

The cerebral protective effect and mechanism of action of vitamin B6 adjuvant ceftriaxone in experimental pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis is one of the most common infectious diseases with a high-mortality rate and long-term neurological sequelae, affecting up to 50% of survivors. Pneumococcal compounds are pro-inflammatory mediators that induce an innate immune response and tryptophan degradation through the kynurenine pathway. Vitamin B6 (vitB6) is an important vitamin which acts as a cofactor at the active sites of enzymes that catalyze a great number of reactions involved in the metabolism of tryptophan through the kynurenine pathway and may thus limit the accumulation of neurotoxic metabolites and preserve the cellular energy status. The aim of this study was to investigate the neuroprotective effect of adjuvant treatment with vitB6 in pneumococcal meningitis. METHODS: The effects of vitB6 on the clinical symptoms, the expression of kynureninase (KYN), Kynurenic acid (KYNA), nicotinamide adenine dinucleotide (NAD) and cytokines in brain tissue and memory of infant Wistar rats subjected to pneumococcal meningitis were researched. At the same time, Kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 was applied in order to further investigate the brain protective effect of vitB6 in bacterial meningitis. RESULTS: Adjuvant therapy of bacterial meningitis with vitB6 could improve the clinical symptoms, learning performance, lead to the maintenance of cellular NAD+ and ATP homeostasis and significantly down-regulate the levels of cytokines in the brain tissue by affecting the KYN pathway. CONCLUSIONS: Adjuvant treatment with vitB6 in pneumococcal meningitis could exert neuroprotective effect via increasing the preservation of cellular energy through affecting the KYN pathway and reducing of the inflammatory response.

Formulation optimization of self-emulsifying preparations of puerarin through self-emulsifying performances evaluation in vitro and pharmacokinetic studies in vivo.

The main purpose of this work is to prepare self-emulsifying drug delivery system (SEDDS) of a poorly water soluble drug, puerarin. Solubility of puerarin was determined in various oils and surfactants. Oleic acid and Tween 80 provided higher solubility. Addition of propylene glycol as cosurfactant improved solubility of puerarin and the spontaneity of self-emulsification. A series of mixtures comprising oleic acid, propylene glycol and Tween 80 were prepared and their self-emulsifying properties were studied. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and particle sizes of the resultant emulsions were determined using a laser diffraction sizer. The pharmacokinetic behaviors of three different SEDDS formulations (F2, F3, F4) were investigated in Beagle dogs. The bioavailability was compared using the pharmacokinetic parameters, peak plasma concentration (C(max)), time to reach peak plasma concentration (T(max)) and total area under the plasma concentration-time curve (AUC(0-t)). AUC(0-t) was significantly higher in formulation F2 group (5.201 +/- 0.511) ng x mL(-1) x h and formulation F3 group (5.174 +/- 0.498) ng x mL (-1) x h than that in formulation F4 group (3.013 +/- 0.623) ng x mL(-1) x h. Also, C(max) was significantly higher in formulation F2 group (1.524 +/- 0.125) ng x mL(-1) and formulation F3 group (1.513 +/- 0.157) ng x mL(-1) than that in formulation F4 group (0.939 +/- 0.089) ng x mL(-1). Further analysis of the data showed a statistically significant difference between F2 and F4 (P < 0.01) as well as F3 and F4 (P < 0.01) with regard to the values of AUC(0-infinity) and C(max) for three SEDDS formulations, but not between those of F2 and F3 (P > 0.05). From these studies, the SEDDS formulation containing oleic acid (17.5%), Tween 80 (34.5%) and propylene glycol (34.5%) (w/w) was selected as an optimized SEDDS formulation of puerarin. The data suggest the potential use of SEDDS to improve oral absorption of puerarin.

Metastasis: an early event in cancer progression.

PURPOSE: Metastasis is the leading cause of death for a majority of cancer patients, and thus the need to understand the biology of metastasis becomes increasingly acute. When metastasis is initiated in tumor progression remains obscure. Better understanding of mechanisms regulating acquisition of metastatic ability in tumor cells will provide novel therapeutic targets and prevention of metastasis in clinics accompanied with the treatment of the primary tumor might be helpful in reducing metastasis-related mortality. METHODS: A literature search was performed in multiple electronic databases. Research papers from clinical reports to experimental studies on metastasis were analyzed. RESULTS: The article discusses tumor heterogeneity and genomic instability in the context of metastasis and tumor cell dissemination. And then we review biological mechanism of metastasis at an early stage in both intracellular (CSCs and CTCs) and extracellular (microenvironment) context. Finally, current development of anti-metastatic therapies is summarized. CONCLUSIONS: Metastasis could be initiated at an early point of tumor progression. Therefore, early intervention on metastasis should be applied among cancer patients in clinical settings.

Prevalent Exon-Intron Structural Changes in the APETALA1/FRUITFULL, SEPALLATA, AGAMOUS-LIKE6, and FLOWERING LOCUS C MADS-Box Gene Subfamilies Provide New Insights into Their Evolution.

AP1/FUL, SEP, AGL6, and FLC subfamily genes play important roles in flower development. The phylogenetic relationships among them, however, have been controversial, which impedes our understanding of the origin and functional divergence of these genes. One possible reason for the controversy may be the problems caused by changes in the exon-intron structure of genes, which, according to recent studies, may generate non-homologous sites and hamper the homology-based sequence alignment. In this study, we first performed exon-by-exon alignments of these and three outgroup subfamilies (SOC1, AG, and STK). Phylogenetic trees reconstructed based on these matrices show improved resolution and better congruence with species phylogeny. In the context of these phylogenies, we traced evolutionary changes of exon-intron structures in each subfamily. We found that structural changes have occurred frequently following gene duplication and speciation events. Notably, exons 7 and 8 (if present) suffered more structural changes than others. With the knowledge of exon-intron structural changes, we generated more reasonable alignments containing all the focal subfamilies. The resulting trees showed that the SEP subfamily is sister to the monophyletic group formed by AP1/FUL and FLC subfamily genes and that the AGL6 subfamily forms a sister group to the three abovementioned subfamilies. Based on this topology, we inferred the evolutionary history of exon-intron structural changes among different subfamilies. Particularly, we found that the eighth exon originated before the divergence of AP1/FUL, FLC, SEP, and AGL6 subfamilies and degenerated in the ancestral FLC-like gene. These results provide new insights into the origin and evolution of the AP1/FUL, FLC, SEP, and AGL6 subfamilies.

Novel spiropyrazolone antitumor scaffold with potent activity: Design, synthesis and structure-activity relationship.

Phenotypic screening of high quality compound library is an effective strategy to discover novel bioactive molecules. Previously, we developed the divergent organocatalytic cascade approach to efficiently construct a focused library with scaffold diversity and successfully identified a novel spiropyrazolone antitumor scaffold. Herein, a series of spiropyrazolone derivatives were designed, synthesized and assayed. Most of them showed good in vitro antitumor activity with a broad spectrum. Preliminary structure-activity relationship for the substitutions and the stereo configuration were obtained. Compound 5k showed good antitumor activity and could effectively induce cancer cell apoptosis, which represents a good starting point for the development of novel antitumor agents.