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DNA damage is a central mechanism in the pathogenesis and treatment of human diseases, notably cancer. Little is known about reductive DNA damage in causing genetic mutations during oncogenesis and killing cancer cells during radiotherapy. The prehydrated electron (e(-)(pre)) has the highest yield among all the radicals generated in cells during ionizing radiation and has subpicosecond lifetimes (10(-13) s) and energies below 0 eV, but its role in DNA damage is unknown. In this work, our real-time measurements by femtosecond time-resolved laser spectroscopy have revealed that while adenine and cytosine can effectively trap an e(-)(pre) to form stable anions, thymidine and especially guanine are highly susceptible to dissociative electron transfer of e(-)(pre), leading to bond dissociation in DNA. Our finding demonstrates a dissociative electron transfer pathway for reductive DNA damage that might be related to various diseases such as cancer and stroke. Moreover, this finding challenges the conventional notion that damage to the genome is mainly induced by the oxidizing OH* radical and might eventually lead to improved radiotherapy of cancer and radioprotection of humans.

Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-␤-estradiol (E2) causes a 3-to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E 2-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CI-1040. In vitro, E 2 inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E 2 enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEKdependent pathways by E 2 leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.L AM, the pulmonary manifestation of tuberous sclerosis complex (TSC), affects women almost exclusively (1). LAM affects 30Ϫ40% of women with TSC (2, 3). In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (4). LAM can also occur in women who do not have germline mutations in TSC1 or TSC2 (sporadic LAM). LAM cells from both TSC-LAM and sporadic LAM carry inactivating mutations in both alleles of the TSC1 or TSC2 genes (5). The protein products of TSC1 and TSC2, hamartin and tuberin, respectively, form heterodimers (6, 7) that inhibit the small GTPase Ras homologue enriched in brain (Rheb), via tuberin's highly conserved GTPase activating domain. In its active form, Rheb activates the mammalian target of rapamycin (mTOR) complex 1 (TORC1), which is a key regulator of protein translation, cell size, and cell proliferation (8). Evidence of TORC1 activation, including hyperphosphorylation of ribosomal protein S6, has been observed in tumor specimens from TSC patients and LAM patients (9-11). Independent of its activation of mTOR, Rheb inhibits the activity of B-Raf and C-Raf/Raf-1 kinase, resulting in reduced phosphorylation of p42/44 MAPK (12-14), but the impact of the Raf/MEK/ MAPK pathway on disease pathogenesis is undefined.LAM is characterized pathologically by widespread proliferation of abnormal smooth muscle cells and by cystic changes within the lung parenchyma (1). About 60% of women with the sporadic form of LAM also have renal angiomyolipomas. The presence of TSC2 mutations in LAM cells and renal angiomyolipoma cells from women with sporadic LAM, but not in normal tissues, has led to the hypothesis that LAM cells spread to the lungs via a metastatic mechanism, despite the fact that LAM cells have a histologically benign appearance (15,16). Genetic and fluorescent in situ hybridization analyses of recurrent LAM after lung transplantation support this benign metastatic model (16).The female...

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

Phytohormones play critical roles in regulating plant responses to stress. We investigated the effects of water stress induced by adding 12% (w/v) polyethylene glycol to the root medium on the levels of abscisic acid (ABA), indole-3-acid (IAA), zeatin (ZT), and gibberellin(3) (GA(3)) in maize leaves. The results suggested that water stress had significant effects on the four hormone levels. There was a transient increase in the IAA content during the initial stage of adaptation to water stress in maize leaves, but it dropped sharply thereafter in response to water stress. ABA content increased dramatically in maize leaves after 24 h of exposure to water stress, and then the high levels of ABA were maintained to the end. The contents of ZT and GA(3) rapidly declined in maize leaves subjected to water stress. The effects of water stress on chlorophyll content, electrolyte leakage and malondialdehyde levels in maize leaves were also studied. The variation of cell damage was negatively correlated with ZT and GA(3) levels in maize leaves under water stress. Thus, we explored the roles of ZT and GA(3) on the growth of maize seedlings under water stress by exogenous application. It is possible that both ZT and GA(3) were effective in protecting maize seedlings from water stress, which would be of great importance for the improvement of drought tolerance in maize by genetic manipulation.

Despite intense study over the past two decades, the dynamics of electron solvation in water, particularly regarding the physical properties and lifetimes of non-equilibrium, incompletely relaxed electrons, remain very controversial. Both experimental and theoretical studies have reported a very diverse range, from approximately 50 to approximately 1000 fs, for the lifetime of the p-like excited state of the hydrated electron, and the nature of incompletely relaxed states remains unclear. Here, we reveal that these controversies are to a great extent due to a hidden effect, i.e., the universal existence of a coherence spike at delay time zero in pump-probe spectroscopic kinetics traces. After removing this spike effect, we show that the intrinsic lifetimes of the two incompletely relaxed states in bulk water are 180+/-30 and 545+/-30 fs, respectively. Moreover, our results using iododeoxyuridine as a molecular probe reveal that both states are electronically excited states of the hydrated electron and the second state of a 545 fs lifetime is the long-sought wet electron. These results resolve the long-standing controversies about electron hydration dynamics.

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