A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Elimination of the differential chemoresistance between the murine B-cell lymphoma LY-ar and LY-as cell lines after arsenic (As2O3) exposure via the overexpression of gsto1 (p28).

PURPOSE: Arsenic, in the form of As(2)O(3), has gained therapeutic importance because it has been shown to be very effective clinically in the treatment of acute promyelocytic leukemia (APL). Via numerous pathways arsenic induces cellular alterations such as induction of apoptosis, inhibition of cellular proliferation, stimulation of differentiation, and inhibition of angiogenesis. Responses vary depending on cell type, dose and the form of arsenic. GSTO1, a member of the glutathione S-transferase superfamily omega, has recently been shown to be identical to the rate-limiting enzyme, monomethyl arsenous (MMA(V)) reductase which catalyzes methylarsonate (MMA(V)) to methylarsenous acid (MMA(III)) during arsenic biotransformation. In this study, we investigated whether arsenic trioxide (As(2)O(3)) induces apoptosis in both chemosensitive and chemoresistant cell lines that varied in their expression of p28 (gsto1), the mouse homolog of GSTO1. METHODS: The cytotoxicity of arsenic in the gsto1- and bcl-2-expressing chemoresistant and radioresistant LY-ar mouse lymphoma cell line, was compared with that of the LY-ar's parental cell line, LY-as. LY-as cells are radiosensitive, apoptotically permissive, and do not express gsto1 or bcl-2. Cell survival, glutathione (GSH) levels, mitochondrial membrane potential, and stress-activated kinase status after arsenic treatment were examined in these cell lines. RESULTS: As(2)O(3) induced an equivalent dose- and time-dependent increase in apoptosis in these cell lines. Cellular survival, as measured after a 24-h exposure, was also the same in each cell line. Reduced GSH was modulated in a similar time- and dose-dependent manner. Apoptosis was preceded by loss of mitochondrial membrane potential that triggered caspase-mediated pathways associated with apoptosis. With a prolonged exposure of As(2)O(3), both cell lines showed decreased activation of ERK family members, ERK1, ERK2 and ERK5. As(2)O(3) enhanced the death signals in LY-ar cells through a decrease in GSH, loss of mitochondrial membrane potential, and abatement of survival signals. This effect is similar to that seen when LY-ar cells are treated with thiol-depleting agents or by the removal of methionine and cysteine (GSH precursor) from the growth medium. This response is also completely contrary to that seen for radiation, actinomycin D, VP-16 and other agents, where LY-ar cells do not succumb to apoptosis. CONCLUSIONS: The overexpression of gsto1 in normally chemoresistant and radioresistant LY-ar cells renders them vulnerable to the cytotoxic effects of As(2)O(3), despite the 30-fold overexpression of the survival factor bcl-2. Gsto1 and its human homolog, GSTO1, may serve as a marker for arsenic sensitivity, particularly in cells that are resistant to other chemotherapeutic agents.

Age-dependent renal accumulation of 4-hydroxy-2-nonenal (HNE)-modified proteins following parenteral administration of ferric nitrilotriacetate commensurate with its differential toxicity: implications for the involvement of HNE-protein adducts in oxidative stress and carcinogenesis.

In this study, we show that the toxicity of ferric nitrilotriacetate (Fe-NTA) can be correlated with the tissue accumulation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts. It is observed that the toxic manifestations of Fe-NTA gradually increase with the increasing age of animals. A dose of Fe-NTA which produces almost 100% mortality in aged rats causes 70% mortality in adults, 30% in pups, 20% in litters, and less than 10% in neonates. The age-dependent increase in its toxicity is also evident from the data of renal microsomal lipid peroxidation and hydrogen peroxide generation. No significant difference in the generation of H2O2 and induction of renal microsomal lipid peroxidation between saline- and Fe-NTA-treated neonates, litters, and pups could be observed. However, in adult rats, a significant increase in both of the parameters was observed which was even greater in aged rats. On the contrary, renal glutathione levels in these animals show an inverse relationship with the oxidant generation. In neonates, litters, and pups the maximum decrease of glutathione was up to 22%, whereas in adult and aged rats, the depletion was more than 60% of their respective saline-treated controls. Parallel to this data, blood urea nitrogen and creatinine, the indicators of renal damage, show a significant increase in Fe-NTA-treated adult and aged rats only, whereas no significant alterations were observed in other groups. Similarly, the magnitude of ODC induction and [3H]thymidine incorporation was much higher in aged and adult rats in comparison to other groups of animals after Fe-NTA treatment. Additionally, the immunohistochemical localization studies show a significant increase in HNE-modified protein adducts in kidney of adult and aged rats, whereas no significant staining was observed in other groups. A similar increase in the level of protein carbonyls has also been observed with the increasing age of rats. These data suggest that the toxicity of Fe-NTA increases with the increasing age of rats and correlates with the accumulation of HNE-modified protein adducts. It may also be speculated that Fe-NTA-mediated renal toxicity leading to carcinogenesis may be related to the tissue accumulation of HNE-modified protein adducts. However, further studies are needed to establish a definite role of HNE-modified proteins in Fe-NTA-mediated carcinogenesis.

Copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Earlier we have shown that ferric-nitrilotriacetate (Fe-NTA) is a hepatic as well as renal tumor promoter and acts by elaborating oxidative stress. In this study we show that copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen. Similar to Fe-NTA, Cu-NTA has an ability to induce hepatic ornithine decarboxylase (ODC) activity dose-dependently. The maximum induction in hepatic ODC activity was observed 12 h after Cu-NTA treatment. However, renal ODC activity showed no significant changes at any time point and dose regimen studied. Similarly, hepatic and renal DNA synthesis which are measured as [3H]thymidine incorporation were increased dose-dependently in both the organs after Cu-NTA treatment. Unlike Fe-NTA, Cu-NTA administration had no significant effect on hepatic and renal glutathione, and on the activities of glutathione reductase, glutathione-S-transferase and catalase. In liver, saline-alone, DEN-alone, Cu-NTA-alone or DEN + Cu-NTA treated animals showed no hepatic tumors. Liver histology from only DEN-initiated and saline-treated control animals showed occasional appearance of a typical cell with large nucleus. Treatment of Cu-NTA to uninitiated and initiated animals showed more or less similar hepatic histology. Treatment of Cu-NTA to DEN-initiated animals resulted in the proliferative changes characterized by extensive hepatocellular hyperplasia. In case of kidney, the treatment of Cu-NTA to both the DEN-initiated and uninitiated animals led to the development of renal cell tumors. Treatment of Cu-NTA to the uninitiated animals produced renal cell tumors in about 18.7% animals. However, treatment of Cu-NTA to the DEN-initiated animals led to the development of renal cell tumors in 77.7% animals, of which most of the tumors were bilateral. However, DEN-initiated and saline-treated control animals showed no evidence of tumors. Our data indicate that Cu-NTA is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Augmentation of 12-O-tetradecanoyl 13-phorbol acetate-mediated tumor promoting response by the porphyrin photosensitization of 7,12-dimethyl benz[a]anthracene-initiated murine skin: role of in situ generated reactive oxygen species.

Recently, we have shown that sustained ROS generation by prolonged porphyrin-mediated photosensitization in murine skin acts as a stage I and weak complete tumor promoter. Further to this, in the present study, we show that porphyrin photosensitization of DMBA-initiated murine skin results in the augmentation of TPA-mediated tumor promoting response. The photosensitization increased tumor yield to 15 tumors per mouse as compared to 7.5 tumors per mouse in the group treated with TPA alone. Further, 100% tumor incidence in the TPA-treated photosensitized group occurred at week 11 whereas it occurred at week 19 in the TPA alone treated group. Porphyrin photosensitization slightly decreased the latency period of TPA-mediated tumor formation by 1 week. The TPA-mediated ODC induction (1300% of saline-treated control) has been augmented in the photosensitized group (1950%). However, the amount of [3H]thymidine incorporation was not significantly different in the photosensitized TPA-treated and TPA alone-treated groups. Similarly, TPA treatment in photosensitized animals augmented the depletion of cutaneous glutathione and enhancement of lipid peroxidation. These changes were attenuated in butylated hydroxytoluene-pretreated animals. Our results suggest that cutaneous porphyrin photosensitization augments TPA-mediated tumor promotion in murine skin.

Potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress.

Many chemical compounds which induce oxidative stress in the tissue produce carcinogenesis either alone or act as a tumor promoter in carcinogen-initiated animals after prolonged exposure. Here, we report that potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. KBrO3 administration dose dependently induced renal ornithine decarboxylase (ODC) activity several fold compared to its activity in saline-treated rats. Similarly renal DNA synthesis which has been measured as [3H]thymidine incorporation in DNA also increases. KBrO3 administration also depleted the level of renal glutathione and glutathione reductase activity in a time dependent manner. The maximum depletion in the levels of renal glutathione and glutathione reductase activity was observed 3 h after KBrO3 treatment which was 60 and 40%, respectively, of saline-treated controls. Parallel to these changes, a sharp increase in the blood urea nitrogen and serum creatinine levels was observed which is indicative of the concurrent renal damage. These results suggest that oxidant generating KBrO3 acts as a potent proliferator of kidney and acts by producing oxidative damage.

Evidence that Fe-NTA-induced renal prostaglandin F2 alpha is responsible for hyperplastic response in kidney: implications for the role of cyclooxygenase-dependent arachidonic acid metabolism in renal tumor promotion.

Oxidative stress in a tissue activates phospholipase A2 which releases free arachidonic acid. In addition, a low grade oxidative tone also stimulates the tissue cyclooxygenase activity. Cyclooxygenase-dependent arachidonic acid metabolites such as PGF 2 alpha are known to play an important role in the development and maintenance of hyperplasia in skin in response to the application of tumor promoters. In this study we show that Fe-NTA, an oxidant renal tumor promoter induces PGF 2 alpha which was maximum at 12 hours after Fe-NTA treatment. However, at all time points studied, the elevated levels of PGF 2 alpha have been observed. As a result of the induction of PGF 2 alpha, the hyperplastic response can also be observed in the histopathology of the tissue. Additionally, an increased incorporation of [3H]thymidine in renal DNA has also been observed. Pretreatment of animals with indomethacin suppresses Fe-NTA-mediated hyperproliferation suggesting a role of cyclooxygenase in Fe-NTA-mediated stimulation of hyperplastic activity. The pretreatment of animals with the chain breaking antioxidants, Vit. E, BHA and BHT were only partially effective in inhibiting Fe-NTA-mediated PGF2 alpha production, further suggesting a role of non-free radical-dependent mechanism in its production. Our data suggest that Fe-NTA-induced PGF2 alpha through the activation of cyclooxygenase is responsible for the development and maintenance of hyperplasia in kidney.

Porphyrin-mediated photosensitization has a weak tumor promoting activity in mouse skin: possible role of in situ-generated reactive oxygen species.

Reactive oxygen species (ROS) have been implicated in skin tumor promotion. Earlier, we showed that porphyrin-mediated cutaneous photosensitization results in the in situ generation of ROS. Recently, we have provided the first in situ evidence for the involvement of ROS in stage I tumor promotion. In this study we further show that in situ-generated ROS act as weak complete tumor promoters in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Papillomas were induced in Swiss albino mice by a single topical application of DMBA as initiator. The promotion was achieved in these mice by the sustained generation of ROS through dihematoporphyrin ether (DHE)-mediated cutaneous photosensitization, which was done once every day (six times a week) for 24 weeks. The first appearance of visible papillomas could be recorded 24 weeks after the initiation. The highest tumor incidence of 60% occurred at a dose of 2.5 mg/kg body wt DHE. Increasing the dose of DHE produced a decrease in the incidence as well as in the number of papillomas. In contrast, the number of carcinomas/mouse increased with increasing dose of DHE. Histopathology of the tumor samples indicated the formation of in situ carcinoma also in skin. ROS generated through DHE-mediated photosensitization resulted in a approximately 3 fold induction of ODC activity 9 h after photosensitization. DHE-mediated photosensitization enhanced [3H]thymidine incorporation in cutaneous DNA in a dose-dependent manner. A maximum 5-fold induction of [3H]thymidine incorporation was observed at a dose of 10 mg/kg body wt DHE. The longer latency period, low incidence of tumor induction, low tumor yield and low induction of ODC activity as compared with TPA represent the weak but complete tumor promoting potential of in situ-generated ROS. The low tumor incidence and tumor yield observed at higher doses of DHE may be due to the ablation of tumors at early stages due to the strong photodynamic action of DHE.Our data indicate that porphyrin-mediated photosensitization has a weak tumor promoting effect in mouse skin and in situ-generated ROS may play an important role in the development of this response.

Novel copper superoxide dismutase mimics and damage mediated by O2.-.

Metabolites of oxygen such as superoxide anions (O2.-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH.) are potentially damaging to biological systems. Univalent reduction of oxygen produces O2.-, which may be converted to H2O2 and OH(.). The biological damage mediated by O2.- can be attenuated by a cytosolic copper- and zinc-containing enzyme known as superoxide dismutase (SOD). Certain transition metal complexes having properties similar to SOD may be useful in suppressing such damage. However, known complexes have either been ineffective in vivo or may have toxic side effects. We prepared mixed-ligand copper complexes of polyamine using biomolecules such as pyridine or imidazoles as secondary ligands. The choice of polyamines and biomolecules was made with the aim of producing products with low toxicity. Our studies suggest that these copper complexes act as mimics of SOD in a variety of O2.(-)-generating systems and may be effective SOD mimics for their usage to abrogate such an injury in biological systems. This manuscript provides a brief state-of-the-art review on SOD mimics including our own studies.

Ferric nitrilotriacetate (Fe-NTA) is a potent hepatic tumor promoter and acts through the generation of oxidative stress.

Fe-NTA is a known renal carcinogen. However, little is known about its carcinogenic potential in liver. In this study we for the first time show that Fe-NTA is a potent hepatic tumor promoter. Fe-NTA administration induced dose dependently the hepatic ornithine decarboxylase (ODC) activity several folds as compared to its activity in the saline-treated rats. Similarly, hepatic DNA synthesis which is measured as [3H]thymidine incorporation in DNA is also increased following Fe-NTA treatment. The effects of Fe-NTA were similar to other tumor promoters not only with respect to inducing ODC activity and [3H]thymidine incorporation in DNA but also in depleting antioxidant armory of the tissue. Fe-NTA depleted levels of glutathione to about 35% of the saline-treated control and activities of antioxidant enzymes catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase decreased significantly (45-55% of saline-treated control). Concomitant with the depletion in antioxidant armory, Fe-NTA augmented hepatic microsomal lipid peroxidation more than three folds. The pretreatment of rats with antioxidants BHA or BHT diminished the observed effects of Fe-NTA. Our data indicate that Fe-NTA is a potent hepatic tumor promoter and acts through a mechanism involving oxidative stress.

Evidence that in situ generated reactive oxygen species act as a potent stage I tumor promoter in mouse skin.

A body of indirect evidence has suggested the involvement of reactive oxygen species (ROS) in tumor promotion. However, direct evidence for the involvement of in situ generated ROS in tumor promotion is lacking at present. This study provides the first in situ evidence for the involvement of ROS in stage I tumor promotion. Earlier we have shown that parenteral administration of Photofrin-II (a mixture of porphyrins) to mice followed by their exposure to visible light generates ROS. In this study we further provide E.S.R. spectral evidence that both O2.- and .OH radicals are generated during tissue photosensitization. The free radicals/ROS generation is followed by the development of cutaneous inflammation which is maximum at six hours after photosensitization and develops in a dose dependent manner. The epidermal myeloperoxidase activity which represents neutrophil infiltration is also increased more than 160% of the control value. The histopathology of skin tissues of 7,12 dimethyl benz(a)anthracene initiated mice receiving multiple treatments of Pf-II and light for a period of four weeks indicates pronounced epidermal hyperplasia, glandular hyperplasia, dark basal keratinocytes induction characterized by the high uptake of the dye and frequent neutrophil infiltrations. Our data indicate that ROS generated in situ as a result of porphyrin-mediated cutaneous photosensitization results in the development of changes characteristic of stage I tumor promotion in murine skin.

Comparison of single, fractionated and hyperfractionated irradiation on the development of normal tissue damage in rat lung.

The effect of fractionated thoracic irradiation on the development of normal tissue damage in rats was compared to that produced by single doses. Animals received a single dose of 15 Gy, 30 Gy in 10 daily fractions of 3 Gy each (fractionation), or 30 Gy in 30 fractions of 1 Gy each 3 times a day (hyperfractionation). The treatments produced minimal lethality since a total of only 6 animals died between days 273 and 475 after the initiation of treatment, with no difference in survival observed between the control and any of the 3 treated groups. Despite the lack of lethality, evidence of lung damage was obtained by histological examination. At times less than 180 days after treatment, the lungs of animals receiving a single dose of 15 Gy displayed more severe changes than did animals from either fractionation group. At longer times after treatment (days 261 and 475), the histological appearances within each group were changed, collagen deposits and fibrosis being the most significant observations. Animals that had received either single doses or fractionated doses had more of the pulmonary parenchyma involved than did animals that had received hyperfractionated doses. We conclude that, in the rat lung model, a total radiation dose of 30 Gy fractionated over 14 days produces no more acute lethality nor damage to lung tissue than does 15 Gy delivered as a single dose. However, long-term effects as evidenced by deposits of collagen and development of fibrosis are significantly reduced by hyperfractionation when compared to single doses and daily fractionation.