From clinical specimens to human cancer preclinical models—a journey the NCI-cell line database—25 years later

The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi-disciplinary team that collaborated to generated large, comprehensively annotated, cell-line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient-donated specimens that have been remarkably valuable for other types of cancer and disease research. A comprehensive analysis conducted by the NCI Center for Research Strategy of the 278 cell lines reported in the original Journal of Cellular Biochemistry Supplement, documents that these cell lines and related products have since been used in more than 14 000 grants, and 33 207 published scientific reports. This has resulted in over 1.2 million citations using at least one cell line. Many publications involve the use of more than one cell line, to understand the value of the resource collectively rather than individually; this method has resulted in 2.9 million citations. In addition, these cell lines have been linked to 422 clinical trials and cited by 4700 patents through publications. For lung cancer alone, the cell lines have been used in the research cited in the development of over 70 National Comprehensive Cancer Network clinical guidelines. Finally, it must be underscored again, that patient altruism enabled the availability of this invaluable research resource.     

The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord

We examined the terminations of sensory afferents in the brainstem and spinal cord of squirrel monkeys and prosimian galagos 4-8 years after a therapeutic forelimb or hindlimb amputation within 2 months of birth. In each animal, the distributions of labeled sensory afferent terminations from remaining body parts proximal to the limb stump were much more extensive than in normal animals. These sprouted afferents extended into the portions of the dorsal horn of the spinal cord as well as the cuneate and external cuneate nuclei of the brainstem (forelimb amputees) or spinal Clarke's column (hindlimb amputee) related to the amputated limb. Such reorganization in sensory afferents along with reorganization of the motor efferents to muscles (Wu and Kaas, J Neurosci 19 : 7679-7697, 1999, Neuron 28 : 967-978, 2000) may provide a basis for mislocated phantom sensations of missing forelimb movements accompanying actual shoulder movements during cortical stimulation or movement imagery in patients with amputations.     

Soil drainage and phosphorus depletion contribute to retrogressive succession along a New Zealand chronosequence

Background and aims

Models of retrogressive succession have emphasised the role of phosphorus (P) depletion in driving biomass loss on surfaces of increasing geologic age, but the influence of impeded drainage on old surfaces has received much less attention. We tested whether poor drainage contributed to changes in ecosystem properties along a 291,000-year chronosequence in New Zealand (the Waitutu chronosequence).

Methods

Soil and ecosystem properties were measured at 24 evenly distributed points within each of eight 1.5 ha plots located on young, intermediate and old surfaces. Regression analyses tested whether drainage, in addition to P, affected ecosystem functioning. A complementary fertilization experiment tested whether P was indeed limiting on the most nutrient-depleted sites.

Results

Most phosphorus depletion occurred in the early stages of pedogenesis (within 24,000 years), and the older surfaces were similar in soil-P contents, whereas drainage was initially good but became increasingly impeded with surface age. In the fertilizer experiment, species showed positive responses to both nitrogen (N) and P addition on the oldest surfaces, supporting Walker and Syer’s model. However, water table depth was also found to be strongly correlated with plant species composition, forest basal area, light transmission, and litter decomposition when comparisons were made across sites, emphasising that it too has strong influences on ecosystem processes.

Conclusions

Poor drainage influences the process of retrogressive succession along the Waitutu chronosequence. We discuss the implications of our work with regard to other chronosequences, suggesting that topography is likely to have strong influences on retrogressive processes.     

Prejudice in the former Soviet Union

Research in the United States and Europe has focused on the prejudice of majority groups towards minority groups, the implication somehow being that majority groups were more prejudiced than minority groups. In the former Soviet Union, ethnic environments were more complex; the same ethnic group could be a majority in one region but a minority in others. Using a sample of 1,459 first‐ and fourth‐year university students from eight regions of the former USSR, this study focuses on Russian, Tatar and Ukrainian respondents (n = 821) to test the hypothesis that the status of an ethnic group (majority/minority) or in‐group bias explains members’ prejudice. According to in‐group bias, all ethnic groups are equally prejudiced, minority and majority alike, whereas group status posits that groups in a majority position are more prejudiced. Findings show that group status has greater impact on prejudice than does in‐group bias. This applies, however, only to Russians. Interpretations of the findings rest on Soviet history and the rise of nationalism during the breakup of the Soviet Union.     

Human TEN1 Maintains Telomere Integrity and Functions in Genome-wide Replication Restart

TEN1 is a component of the mammalian CTC1-STN1-TEN1 complex. CTC1 and/or STN1 functions in telomere duplex replication, C-strand fill-in, and genome-wide restart of replication following fork stalling. Here we examine the role of human TEN1 and ask whether it also functions as a specialized replication factor. TEN1 depletion causes an increase in multitelomere fluorescent in situ hybridization (FISH) signals similar to that observed after CTC1 or STN1 depletion. However, TEN1 depletion also results in increased telomere loss. This loss is not accompanied by increased telomere deprotection, recombination, or T-circle release. Thus, it appears that both the multiple telomere signals and telomere loss stem from problems in telomere duplex replication. TEN1 depletion can also affect telomere length, but whether telomeres lengthen or shorten is cell line-dependent. Like CTC1 and STN1, TEN1 is needed for G-overhang processing. Depletion of TEN1 does not effect overhang elongation in mid-S phase, but it delays overhang shortening in late S/G₂. These results indicate a role for TEN1 in C-strand fill-in but do not support a direct role in telomerase regulation. Finally, TEN1 depletion causes a decrease in genome-wide replication restart following fork stalling similar to that observed after STN1 depletion. However, anaphase bridge formation is more severe than with CTC1 or STN1 depletion. Our findings indicate that TEN1 likely functions in conjunction with CTC1 and STN1 at the telomere and elsewhere in the genome. They also raise the possibility that TEN1 has additional roles and indicate that TEN1/CTC1-STN1-TEN1 helps solve a wide range of challenges to the replication machinery.     

Maize chromosomal knobs are located in gene-dense areas and suppress local recombination

Knobs are conspicuous heterochromatic regions found on the chromosomes of maize and its relatives. The number, locations, and sizes of knobs vary dramatically, with most lines containing between four and eight knobs in mid-arm positions. Prior data suggest that some knobs may reduce recombination. However, comprehensive tests have not been carried out, primarily because most knobs have not been placed on the genetic map. We used fluorescent in situ hybridization and two recombinant inbred populations to map seven knobs and to accurately place three knobs from the B73 inbred on the genomic sequence assembly. The data show that knobs lie in gene-dense regions of the maize genome. Comparisons to 23 other recombinant inbred populations segregating for knobs at the same sites confirm that large knobs can locally reduce crossing over by as much as twofold on a cM/Mb scale. These effects do not extend beyond regions ~10 cM to either side of knobs and do not appear to affect linkage disequilibrium among genes within and near knob repeat regions of the B73 RefGen_v2 assembly.     

Nonbenzamidine acylsulfonamide tissue factor–factor VIIa inhibitors

Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.     

Design and synthesis of MMP inhibitors with appended fluorescent tags for imaging and visualization of matrix metalloproteinase enzymes

We describe the synthesis, MMP-2 and 9 potency, and in vitro evaluation of a series of α-sulfone hydroxmate MMP inhibitors conjugated to a series of dyes with different absorption/emission lamina maxima’s that can be used to visualize tumors.