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In this article we present results of a comprehensive review of principal leadership assessment practices in the United States. Our analyses of both the general content and the usage of 65 instruments, 56 at the district level and 9 at the state level, provided an in-depth look at what and how districts and states evaluate principals. Using the learning-centered leadership framework, we focused on identifying the congruence (or lack thereof) between documented assessment practices and the research-based criteria for effective leadership that are associated with improved school performance. Using an iterative and deductive process for instrument content analysis, we found that states and districts focused on a variety of performance areas (e.g., management, external environment, or personal traits) when evaluating their principals, with different formats at various levels of specificity. We also found very limited coverage of leadership behaviors that ensure rigorous curriculum and quality instruction, which are linked with schoolwide improvement for the ultimate purpose of enhanced student learning. In seeking information on how principals are evaluated, we found that in most cases, the practices of leadership assessment lacked justification and documentation in terms of the utility, psychometric properties, and accuracy of the instruments. [ABSTRACT FROM AUTHOR]

Background: Suicidal thoughts and behaviors often emerge in a predictable sequence, with suicidal ideation (SI) preceding planning, and planning preceding actions. Few studies, however, have considered the timing and duration of non-suicidal self-injury (NSSI) in these transitions. Accordingly, this study examined: 1) the developmental sequencing of NSSI, SI and suicide attempts, and 2) whether age of onset or duration predict transitions from NSSI to other SITB, and from SI to NSSI., Methods: 704 first-year students from a mid-sized Canadian university (Sample 1) and 2095 adults from an online research volunteer panel (Sample 2) completed the Self-Injurious Thoughts and Behaviors Interview self-report, which assessed the presence, age of onset, and recency of SITB., Results: NSSI and SI typically onset before age 15, while suicide planning and attempt usually began at or after age 15. Transition from NSSI to SI was likeliest in the first year after NSSI onset. Transition from NSSI to suicide attempt was likeliest in the second and third year after NSSI onset in Sample 1, and up to four years after NSSI onset in Sample 2. Early (before age 13) and late (after age 16) onsets of NSSI predicted higher odds of transitioning from NSSI to SI or attempt. Transition from SI to NSSI was likeliest in the first two years after SI onset and when SI began before age 13., Conclusions: The first year after NSSI or SI onset are critical for transitions to other SITB. Targeted prevention and monitoring should be considered for people who recently initiated NSSI., Competing Interests: Declaration of competing interest The authors declare none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Disrupted sleep has been linked to suicidal thoughts and behavior. Less is known, however, about the underlying mechanisms of this relationship. A more nuanced understanding of the link between sleep and suicide may help inform treatment decisions and the development of prevention and intervention strategies. The present study examined daily average sleepiness as a moderator to the relation between same-day passive and active suicide ideation (SI). Fifty-nine young adults (mean age = 21.04; SD = 2.22) endorsing SI at least twice in the two weeks prior to baseline completed 3-5 daily surveys of sleepiness and SI over 2 weeks as part of a broader study. Across several indicators of sleepiness (desire to stay awake, desire to fall asleep), passive SI (desire to die, desire to live), and active SI (occurrence, intensity, duration, and controllability), the overall findings demonstrated that daily average sleepiness magnified the relation between same-day passive SI and active SI severity. These findings indicate that being sleepier than usual may increase the likelihood that passive SI transitions to active SI. Future research is needed to test the causal influence of sleepiness on this transition., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report or disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To clarify the role of age in risk associated with drug misuse and binge drinking, this study examines the differential relations of binge drinking and prescription drug misuse to risk of suicidal ideation and attempts in young adults of college age (18-24) compared to those above the age of 25., Methods: We used data from the National Survey on Drug Use and Health (NSDUH) for the years 2015 through 2019 (N = 269,078)., Results: The study found that, for adults above college age, the presence of any past-month binge drinking was associated with a higher likelihood of past-year suicide ideation (b = 0.427, OR = 1.532, 95%CI [1.388, 1.692]) and attempts (b = 0.637, OR = 1.891, 95%CI [1.271, 2.813]) compared to college-aged adults. Similarly, past-month prescription drug misuse showed stronger associations with past-year suicide ideation (b = 0.831, OR = 2.297, 95%CI [1.952, 2.701]) and attempts (b = 0.539, OR = 1.715, 95%CI [1.264, 2.327]) in adults above college age., Conclusion: These findings highlight that binge drinking and prescription drug misuse appears to become more strongly associated with suicide ideation and attempts after adults age beyond young adulthood., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report or disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This article examined the discriminant and convergent validity of commonly used self-report measures of self-criticism, self-esteem, and shame. A confirmatory factor analysis (CFA) using multiple self-report measures of each construct showed low levels of discriminant validity between self-reported self-esteem, shame, and self-criticism and instead demonstrated correspondingly high levels of shared variance. However, bifactor analyses on the items across each measure suggested that self-report measures of self-esteem, shame, and self-criticism may contain distinct characteristics that are underrepresented in current measures of each construct. Based on the factor loadings in item-level bifactor analyses, a new measure, the Negative Self-Evaluation Scale (NSES), was constructed to improve the assessment of the unique characteristics of shame, self-esteem, and self-criticism. Implications for current and future practices concerning the measurement of each construct are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

This paper examined the unique associations of latent self-esteem with symptoms of depression, over-and-above latent shame-proneness (study 1) and latent self-criticism (study 2), among two samples of undergraduate students. In study 1, confirmatory factor analysis (CFA) showed convergent and discriminant validity for most measures of shame-proneness and self-esteem. Shame-proneness and self-esteem (taken separately) were strongly related to depressive symptoms. Controlling for each other, self-esteem but not shame-proneness remained associated with depressive symptoms. In study 2, CFA showed convergent validity but not discriminant validity for measures of self-criticism and low self-esteem. Self-esteem and self-criticism (taken separately) were strongly related to depressive symptoms. Controlling for each other, however, neither construct was significantly associated with depressive symptoms. Findings suggest that (a) self-esteem and shame-proneness have good discriminant validity, (b) self-esteem is uniquely related to depressive symptoms above and beyond shame-proneness, and (c) self-report measures of self-criticism and self-esteem have poor discriminant validity., Competing Interests: Conflict of Interest: None of the authors have any conflicts of interest to report.

Type II topoisomerase enzymes are essential for resolving DNA topology problems arising through various aspects of DNA metabolism. In vertebrates two isoforms are present, one of which (TOP2A) accumulates on chromatin during mitosis. Moreover, TOP2A targets the mitotic centromere during prophase, persisting there until anaphase onset. It is the catalytically-dispensable C-terminal domain of TOP2 that is crucial in determining this isoform-specific behaviour. In this study we show that, in addition to the recently identified chromatin tether domain, several other features of the alpha-C-Terminal Domain (CTD). influence the mitotic localisation of TOP2A. Lysine 1240 is a major SUMOylation target in cycling human cells and the efficiency of this modification appears to be influenced by T1244 and S1247 phosphorylation. Replacement of K1240 by arginine results in fewer cells displaying centromeric TOP2A accumulation during prometaphase-metaphase. The same phenotype is displayed by cells expressing TOP2A in which either of the mitotic phosphorylation sites S1213 or S1247 has been substituted by alanine. Conversely, constitutive modification of TOP2A by fusion to SUMO2 exerts the opposite effect. FRAP analysis of protein mobility indicates that post-translational modification of TOP2A can influence the enzyme's residence time on mitotic chromatin, as well as its subcellular localisation.

We examined the relation of interpersonal and media exposure to nonsuicidal self-injury (NSSI) among 340 university students in the southeastern United States (73.5% female, M age = 19.38 years, SD = 1.15). We also assessed interactions and main effects of each exposure and emotion dysregulation in relation to NSSI, testing the social learning hypothesis of NSSI. Most participants endorsed medium to high levels of exposure to NSSI via media sources. More than one-third of participants were somewhat or very familiar with someone who engaged in NSSI. Almost half reported occasional or frequent conversations about NSSI. Both exposure forms were significantly related to NSSI history. However, hurdle regression analyses revealed that interpersonal exposure and emotion dysregulation, but not media exposure, were significantly associated with NSSI history and frequency. We did not find evidence for an emotion dysregulation-by-interpersonal-exposure interaction. We discuss implications for theoretical models of NSSI, limitations, and future directions., (Copyright © 2017. Published by Elsevier Ltd.)

Understanding the mechanisms of chromosomal double-strand break repair (DSBR) provides insight into genome instability, oncogenesis and genome engineering, including disease gene correction. Research into DSBR exploits rare-cutting endonucleases to cleave exogenous reporter constructs integrated into the genome. Multiple reporter constructs have been developed to detect various DSBR pathways. Here, using a single endogenous reporter gene, the X-chromosomal disease gene encoding hypoxanthine phosphoribosyltransferase (HPRT), we monitor the relative utilization of three DSBR pathways following cleavage by I-SceI or CRISPR/Cas9 nucleases. For I-SceI, our estimated frequencies of accurate or mutagenic non-homologous end-joining and gene correction by homologous recombination are 4.1, 1.5 and 0.16%, respectively. Unexpectedly, I-SceI and Cas9 induced markedly different DSBR profiles. Also, using an I-SceI-sensitive HPRT minigene, we show that gene correction is more efficient when using long double-stranded DNA than single- or double-stranded oligonucleotides. Finally, using both endogenous HPRT and exogenous reporters, we validate novel cell cycle phase-specific I-SceI derivatives for investigating cell cycle variations in DSBR. The results obtained using these novel approaches provide new insights into template design for gene correction and the relationships between multiple DSBR pathways at a single endogenous disease gene., (© The Author 2015. Published by Oxford University Press.)

The correction of disease-causing mutations by single-strand oligonucleotide-templated DNA repair (ssOR) is an attractive approach to gene therapy, but major improvements in ssOR efficiency and consistency are needed. The mechanism of ssOR is poorly understood but may involve annealing of oligonucleotides to transiently exposed single-stranded regions in the target duplex. In bacteria and yeast it has been shown that ssOR is promoted by expression of Redβ, a single-strand DNA annealing protein from bacteriophage lambda. Here we show that Redβ expression is well tolerated in a human cell line where it consistently promotes ssOR. By use of short interfering RNA, we also show that ssOR is stimulated by the transient depletion of the endogenous DNA mismatch repair protein MSH2. Furthermore, we find that the effects of Redβ expression and MSH2 depletion on ssOR can be combined with a degree of cooperativity. These results suggest that oligonucleotide annealing and mismatch recognition are distinct but interdependent events in ssOR that can be usefully modulated in gene correction strategies.

Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The EGF receptor (EGFR) is therapeutically targeted by antibodies and small molecules in solid tumors including lung, colorectal, and breast cancer. However, chemotherapy remains important, and efforts to improve efficacy through combination with targeted agents is challenging. This study examined the effects of short and long durations of exposure to the EGFR- and HER2-targeted tyrosine kinase inhibitors (TKI) gefitinib and lapatinib, on induction of cell death and DNA damage by topoisomerase IIα (Topo IIα) poisons, in the SK-Br-3 HER2-amplified breast cancer cell line. Short exposure to either gefitinib or lapatinib for 1 hour did not affect the induction of apoptosis by the Topo IIα poisons doxorubicin, etoposide, and m-AMSA. In contrast, cells treated for 48 hours were resistant to all three drugs. Short exposure (1 hour) to TKI did not alter the number of DNA single- or double-strand breaks (DSB) induced, whereas longer exposure (48 hours) reduced the number of DNA DSBs and the formation of γ-H2AX foci. Both gefitinib and lapatinib reduced the expression and activity of Topo IIα at 48 hours. Studies using a cell line with inducible downregulation of Topo IIα showed that expression of Topo IIα, and not Topo IIβ, determined the number of DNA strand breaks induced by these chemotherapeutic agents. These results indicate that prolonged exposure to TKIs targeting EGFR and HER2 induce resistance to doxorubicin, etoposide, and m-AMSA through downregulation of Topo IIα. This may explain why their addition to chemotherapy regimens have not increased efficacy., (©2013 AACR.)

Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. Cdk1 promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds. We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in Cdk1 activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid Cdk1 activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a Cdk1 inhibitors.

Coadministration of the iron chelator dexrazoxane reduces by 80% the incidence of heart failure in cancer patients treated with anthracyclines. The clinical application of dexrazoxane is limited, however, because its ability to inhibit topoisomerase IIα (TOP2A) is feared to adversely affect anthracycline chemotherapy, which involves TOP2A-mediated generation of DNA double-strand breaks (DSB). Here, we investigated the apoptotic effects of dexrazoxane and the anthracycline doxorubicin, alone and in combination, in a tumor cell line with conditionally regulated expression of TOP2A. Each drug caused apoptosis that was only partly dependent on TOP2A. Unexpectedly, dexrazoxane was found to cause TOP2A depletion, thereby reducing the doxorubicin-induced accumulation of DSB. Despite this latter effect, dexrazoxane showed no adverse effect on doxorubicin-induced apoptosis. This could be explained by the TOP2A-independent apoptotic effects of each drug: those of doxorubicin included TOP2A-independent DSB formation and depletion of intracellular glutathione, whereas those of dexrazoxane were caspase independent. In conclusion, both doxorubicin and dexrazoxane induce apoptosis via TOP2A-dependent and TOP2A-independent mechanisms, the latter compensating for the reduction in cell killing due to dexrazoxane-induced TOP2A depletion. These observations suggest an explanation for the absence of adverse dexrazoxane effects on clinical responses to doxorubicin.

Eukaryotic type II topoisomerases (Topo II) are implicated in a wide range of cellular processes. Cells in which Topo II protein has been specifically depleted or mutated provide powerful systems for analysing the normal in vivo functions of Topo II proteins and for assessing their roles in various chemotherapy regimens. Summarised here are the ways in which Topo II has been depleted or mutated in animal cells and the type of information gleaned. The cell lines generated are tabulated and represent a useful resource for further in vivo studies of Topo II function, one that we expect to grow in size and utility in the coming years.

Chromosomal correction of dystrophin gene mutations is a most desirable therapeutic solution for Duchenne muscular dystrophy, as it allows production of the full-length dystrophin under the control of locus-specific promoters. Here we explored gene targeting in conditionally immortal mouse dystrophin-deficient myoblasts. We constructed an adenoviral vector for the correction of the mdx mutation, containing 6.0 kb of sequence homologous to the target locus (partial intron 21 through to exon 24 with the normal sequence of exon 23) and a neomycin expression cassette inserted in intron 23. Adenovirus-based gene targeting was previously reported to be beneficial in mouse embryonic stem cells, resulting in one targeted integration per three integration events. However, we found no targeted integration events among 144 stably transduced G418-resistant myoblast clones, reflecting efficient random integration of the adenoviral vector in myogenic cells. We found that mouse myoblasts are capable of integrating recombinant adenoviral DNA with an efficiency approaching 1%. Interestingly, dermal fibroblasts integrate adenoviral DNA up to 100 times less efficiently than myoblasts from the same mice. We also show that the efficiency of recombinant adenoviral DNA integration is influenced by preinfection cell density, possibly indicating the importance of cellular DNA replication for adenoviral integration.

SUMOylation is essential for cell-cycle regulation in invertebrates; however, its functions during the mammalian cell cycle are largely uncharacterized. Mammals express three SUMO paralogs: SUMO-1, SUMO-2, and SUMO-3 (SUMO-2 and SUMO-3 are 96% identical and referred to as SUMO-2/3). We found that SUMO-2/3 localize to centromeres and condensed chromosomes, whereas SUMO-1 localizes to the mitotic spindle and spindle midzone, indicating that SUMO paralogs regulate distinct mitotic processes in mammalian cells. Consistent with this, global inhibition of SUMOylation caused a prometaphase arrest due to defects in targeting the microtubule motor protein CENP-E to kinetochores. CENP-E was found to be modified specifically by SUMO-2/3 and to possess SUMO-2/3 polymeric chain-binding activity essential for kinetochore localization. Our findings indicate that SUMOylation is a key regulator of the mammalian cell cycle, with SUMO-1 and SUMO-2/3 modification of different proteins regulating distinct processes.

Topoisomerase II removes supercoils and catenanes generated during DNA metabolic processes such as transcription and replication. Vertebrate cells express two genetically distinct isoforms (alpha and beta) with similar structures and biochemical activities but different biological roles. Topoisomerase IIalpha is essential for cell proliferation, whereas topoisomerase IIbeta is required only for aspects of nerve growth and brain development. To identify the structural features responsible for these differences, we exchanged the divergent C-terminal regions (CTRs) of the two human isoforms (alpha 1173-1531 and beta 1186-1621) and tested the resulting hybrids for complementation of a conditional topoisomerase IIalpha knockout in human cells. Proliferation was fully supported by all enzymes bearing the alpha CTR. The alpha CTR also promoted chromosome binding of both enzyme cores, and was by itself chromosome-bound, suggesting a role in enzyme targeting during mitosis. In contrast, enzymes bearing the beta CTR supported proliferation only rarely and when expressed at unusually high levels. A similar analysis of the divergent N-terminal regions (alpha 1-27 and beta 1-43) revealed no role in isoform-specific functions. Our results show that it is the CTRs of human topoisomerase II that determine their isoform-specific functions in proliferating cells. They also indicate persistence of some functional redundancy between the two isoforms.

The full power of gene modification in higher eukaryotes, including its potential to correct disease-causing mutations, has so far been limited by its low efficiency. Now that power looks set to be released through the use of customized endonuclease "hands," DNA-binding zinc fingers linked to nuclease "thumbs," capable of grasping and cutting any chosen genomic target locus. Once cleaved, the target locus is efficiently repaired by endogenous mechanisms, using an exogenous DNA template that carries the chosen modification. These helping hands are likely to touch many areas of biological and clinical endeavor.

DNA Topoisomerase IIalpha (topoIIalpha) is a DNA decatenating enzyme, abundant constituent of mammalian mitotic chromosomes, and target of numerous antitumor drugs, but its exact role in chromosome structure and dynamics is unclear. In a powerful new approach to this important problem, with significant advantages over the use of topoII inhibitors or RNA interference, we have generated and characterized a human cell line (HTETOP) in which >99.5% topoIIalpha expression can be silenced in all cells by the addition of tetracycline. TopoIIalpha-depleted HTETOP cells enter mitosis and undergo chromosome condensation, albeit with delayed kinetics, but normal anaphases and cytokineses are completely prevented, and all cells die, some becoming polyploid in the process. Cells can be rescued by expression of topoIIalpha fused to green fluorescent protein (GFP), even when certain phosphorylation sites have been mutated, but not when the catalytic residue Y805 is mutated. Thus, in addition to validating GFP-tagged topoIIalpha as an indicator for endogenous topoIIalpha dynamics, our analyses provide new evidence that topoIIalpha plays a largely redundant role in chromosome condensation, but an essential catalytic role in chromosome segregation that cannot be complemented by topoIIbeta and does not require phosphorylation at serine residues 1106, 1247, 1354, or 1393.

We have generated mice null for IFN-beta and report the diverse consequences of IFN-beta for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN-beta-/- mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor alpha production, relative to IFN-beta+/+ mice. Notably, constitutive and induced expression of tumor necrosis factor alpha is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-beta-/- mice. We also observe an altered splenic architecture in IFN-beta-/- mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-beta-/- mice, associated with a decrease in B220+ve/high/CD43-ve BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN-beta-/- mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocyte-macrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN-beta-/- background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-beta-/- mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-beta is required during different stages of maturation in the development of the immune system.

Human HT2-19 cells with a conditional cdk1 mutation stop dividing upon cdk1 inactivation and undergo multiple rounds of endoreplication. We show herein that major cell cycle events remain synchronized in these endoreplicating cells. DNA replication alternates with gap phases and cell cycle-specific cyclin E expression is maintained. Centrosomes duplicate in synchrony with chromosome replication, giving rise to polyploid cells with multiple centrosomes. Centrosome migration, a typical prophase event, also takes place in endoreplicating cells. The timing of these events is unaffected by cdk1 inactivation compared with normally dividing cells. Nuclear lamina breakdown, in contrast, previously shown to be dependent on cdk1, does not take place in endoreplicating HT2-19 cells. Moreover, breakdown of all other major components of the nuclear lamina, like the inner nuclear membrane proteins and nuclear pore complexes, seems also to depend on cdk1. Interestingly, the APC/C ubiquitin ligase is activated in these endoreplicating cells by fzr but not by fzy. The oscillations of interphase events are thus independent of cdk1 and of mitosis but may depend on APC/Cfzr activity.

A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabilization engenders a survival pathway that depends on elevated activity of p34(cdc2) kinase and increased expression of the apoptosis inhibitor and mitotic regulator, survivin. Pharmacologic, genetic, or molecular ablation of p34(cdc2) kinase after microtubule stabilization resulted in massive apoptosis independent of p53, suppression of tumor growth, and indefinite survival without toxicity in mice. By ablating this survival checkpoint, inhibitors of p34(cdc2) kinase could safely improve the efficacy of microtubule-stabilizing agents used to treat common cancers.