Diffusion of activated ATM explains γH2AX and MDC1 spread beyond the DNA damage site.

During DNA repair, ATM-induced H2AX histone phosphorylation and MDC1 recruitment spread megabases beyond the damage site. While loop extrusion has been suggested to drive this spread, the underlying mechanism remains unclear. Herein, we provide two lines of evidence that loop extrusion is not the only driver of damage-induced γH2AX spread.

Apoptotic cells may drive cell death in hair follicles during their regression cycle.

Intravital microscopy in live mice has shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays essential role in death induction. Because the DP cells are not necessary for completion of the cycle but only for its initiation it is still an open question what is the mechanism leading to the propagation of apoptosis towards the regenerative stem cell population.

Drug resistant cells with very large proliferative potential grow exponentially in metastatic prostate cancer.

Most metastatic cancers develop drug resistance during treatment and continue to grow, driven by a subpopulation of cancer cells unresponsive to the therapy being administered. There is evidence that metastases are formed by phenotypically plastic cancer cells with stem-cell like properties. Currently the population structure and growth dynamics of the resulting metastatic tumors is unknown.

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA.

Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool.

Tissue homeostasis is achieved through a balance of cell production (growth) and elimination (regression). In contrast to tissue growth, the cells and molecular signals required for tissue regression remain unknown. To investigate physiological tissue regression, we use the mouse hair follicle, which cycles stereotypically between phases of growth and regression while maintaining a pool of stem cells to perpetuate tissue regeneration.

Therapies with diverse mechanisms of action kill cells by a similar exponential process in advanced cancers.

Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor.

Scientific priorities for the BRAIN Initiative.

We present a summary of the scientific deliberations and major conclusions that arose from a workshop on the BRAIN Initiative.

Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma.

Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival.

Hazard ratios in cancer clinical trials--a primer.

The increase and diversity of clinical trial data has resulted in a greater reliance on statistical analyses to discern value. Assessing differences between two similar survival curves can pose a challenge for those without formal training in statistical interpretation; therefore, there has been an increased reliance on hazard ratios often to the exclusion of more-traditional survival measures. However, because a hazard ratio lacks dimensions it can only inform the reader about the reliability and uniformity of the data.

Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche.

Telomere loss at each cell replication limits the proliferative capacity of normal cells, including adult stem cells. Entering replicative senescence protects dividing cells from neoplastic transformation, but also contributes to aging of the tissue. Recent experiments have shown that intestinal mouse stem cells divide symmetrically, at random make decisions to remain stem cells or to differentiate, and gradually lose telomeric DNA.

Telomere sister chromatid exchange and the process of aging.

Telomeres are a hotspot for sister chromatid exchange (T-SCE). Any biological consequence of this form of instability remained obscure until quantitative modeling revealed a link between elevated T-SCE rates and accelerated cellular replicative senescence. This work strongly suggests that progressive telomere erosion is not the only determinant of replicative capacity; instead, T-SCE need to be considered as an independent factor controlling colony growth and senescence.

Hyper telomere recombination accelerates replicative senescence and may promote premature aging.

Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.

Biophysical modeling of phase changes in BOLD fMRI.

In BOLD fMRI, stimulus related phase changes have been repeatedly observed in humans. However, virtually all fMRI processing utilizes the magnitude information only, while ignoring the phase. This results in an unnecessary loss of physiological information and signal-to-noise efficiency.

Cell proliferation in the presence of telomerase.

Background: Telomerase, which is active early in development and later in stem and germline cells, is also active in the majority of human cancers. One of the known functions of telomerase is to extend the ends of linear chromosomes, countering their gradual shortening at each cell division due to the end replication problem and postreplication processing. Telomerase concentration levels vary between different cell types as well as between different tumors.

Versatile protection from mutagenic DNA lesions conferred by bipartite recognition in nucleotide excision repair.

Nucleotide excision repair is a cut-and-patch pathway that eliminates potentially mutagenic DNA lesions caused by ultraviolet light, electrophilic chemicals, oxygen radicals and many other genetic insults. Unlike antigen recognition by the immune system, which employs billions of immunoglobulins and T-cell receptors, the nucleotide excision repair complex relies on just a few generic factors to detect an extremely wide range of DNA adducts. This molecular versatility is achieved by a bipartite strategy initiated by the detection of abnormal strand fluctuations, followed by the localization of injured residues through an enzymatic scanning process coupled to DNA unwinding.

Telomere exchange and asymmetric segregation of chromosomes can account for the unlimited proliferative potential of ALT cell populations.

Telomerase-negative cancer cells show increased telomere sister chromatid exchange (T-SCE) rates, a phenomenon that has been associated with an alternative lengthening of telomeres (ALT) mechanism for maintaining telomeres in this subset of cancers. Here we examine whether or not T-SCE can maintain telomeres in human cells using a combinatorial model capable of describing how telomere lengths evolve over time. Our results show that random T-SCE is unlikely to be the mechanism of telomere maintenance of ALT human cells, but that increased T-SCE rates combined with a recently proposed novel mechanism of non-random segregation of chromosomes with long telomeres preferentially into the same daughter cell during cell division can stabilize chromosome ends in ALT cancers.

DNA repair triggered by sensors of helical dynamics.

Nucleotide excision repair is a constitutive stress response that eliminates DNA lesions induced by multiple genotoxic agents. Unlike the immune system, which generates billions of immunoglobulins and T cell receptors for antigen recognition, the nucleotide excision repair complex uses only a few generic factors to detect an astounding diversity of DNA modifications. New data favor an unexpected strategy whereby damage recognition is initiated by the detection of abnormal oscillations in the undamaged strand opposite to DNA lesions.

Acoustic attenuation probe for Fermion superfluidity in ultracold-atom gases.

Dilute gas Bose-Einstein condensates (BEC's), currently used to cool fermionic atoms in atom traps, can also probe the superfluidity of these fermions. The damping rate of BEC-acoustic excitations (phonon modes), measured in the middle of the trap as a function of the phonon momentum, yields an unambiguous signature of BCS-like superfluidity, provides a measurement of the superfluid gap parameter, and gives an estimate of the size of the Cooper pairs in the BEC-BCS crossover regime. We also predict kinks in the momentum dependence of the damping rate which can reveal detailed information about the fermion quasiparticle dispersion relation.

Density and spin response functions in ultracold fermionic atom gases.

We propose a new method of detecting the onset of superfluidity in a two-component ultracold fermionic gas of atoms governed by an attractive short-range interaction. By studying the two-body correlation functions we find that a measurement of the momentum distribution of the density and spin-response functions allows one to access separately the normal and anomalous densities. The change in sign at low momentum transfer of the normal-ordered part of the density response function signals the transition between a BEC and a BCS regime, characterized by small and large pairs, respectively.