@article{yan_gaddameedhi_sobol_2024, title={Inspiring basic and applied research in genome integrity mechanisms: Dedication to Samuel H. Wilson}, url={https://doi.org/10.1002/em.22595}, DOI={10.1002/em.22595}, abstractNote={Abstract This Special Issue (SI) of Environmental and Molecular Mutagenesis (EMM), entitled “Inspiring Basic and Applied Research in Genome Integrity Mechanisms,” is to update the community on recent findings and advances on genome integrity mechanisms with emphasis on their importance for basic and environmental health sciences. This SI includes two research articles, one brief research communication, and four reviews that highlight cutting edge research findings and perspectives, from both established leaders and junior trainees, on DNA repair mechanisms. In particular, the authors provided an updated understanding on several distinct enzymes (e.g., DNA polymerase beta, DNA polymerase theta, DNA glycosylase NEIL2) and the associated molecular mechanisms in base excision repair, nucleotide excision repair, and microhomology‐mediated end joining of double‐strand breaks. In addition, genome‐wide sequencing analysis or site‐specific mutational signature analysis of DNA lesions from environmental mutagens (e.g., UV light and aflatoxin) provide further characterization and sequence context impact of DNA damage and mutations. This SI is dedicated to the legacy of Dr. Samuel H. Wilson from the U.S. National Institute of Environmental Health Sciences at the National Institutes of Health.}, journal={Environmental and Molecular Mutagenesis}, author={Yan, Shan and Gaddameedhi, Shobhan and Sobol, Robert W.}, year={2024}, month={Apr} }
 @article{mishra_gaddameedhi_2023, title={A new role of TRPM8 in circadian rhythm and molecular clock}, volume={1}, ISSN={["1748-1716"]}, url={https://doi.org/10.1111/apha.13934}, DOI={10.1111/apha.13934}, abstractNote={Over the past decades, studies of the TRPM8 channel, a nonselective cation channel, have provided much insight into the fundamental mechanisms of sensory neuron function that lead to the detection of cold sensors. In the current issue of Acta Physiologica, Reimundez et al1 provide evidence of a novel role of TRPM8 in circadian function in mice. The TRPM (transient receptor potential ion channels, where “m” stands for melastatin) is a family of eight different channels, TRPM1TRPM8.2 The TRPM8 is a cold sensor and is also activated by chemical ligands such as menthol and icilin, but recently, their role in maintaining core body temperature has also been recognized.3,4 TRPM8 is expressed in sensory neurons whose axonal afferents innervate peripheral tissues such as skin and oral cavity. Still, it has not been detected in the brain and spinal cord. Besides nerve tissues, TRPM8 is expressed in tissues such as the prostate, bladder, lungs, and urogenital tract. However, other than the sensory nervous system, the functional role of TRPM8 channels is not well understood. In this issue of Acta Physiologica, Reimundez et al1 provide solid experimental evidence for such a novel mechanism— where they demonstrate that TRPM8 might regulate Period 2 (Per2) mRNA levels in central clock (SCN) and peripheral clock (liver and white adipose tissue) and the circadian regulation of core body temperature. Their publication is among the most significant advances in the field of circadian regulation using cold sensors— it will probably set up the stage for several future research activities in which Reimundez and colleagues' ideas will be rigorously dissected and probed in circadian biology research. Previously, Ordás et al5 demonstrated the presence of TRPM8 fibers in the suprachiasmatic nucleus of the hypothalamus (SCN) of the brain, which is the principal circadian pacemaker in mammals and host a range of other physiological processes such as circadian oscillation, autonomic/peripheral and central nervous system function, regulating core body temperature and sleep– wake cycle. Since SCN receives axonal projections mainly from intrinsically photosensitive retinal ganglion cells (ipRGCs) that are responsible for resetting the circadian clock through SCN neuron activity with light as a primary zeitgeber.6 Here, authors used conventional PCR and mouse reporter lines to show the expression of TRPM8 in the inner retina, specifically in the ganglion cell layer (GC) and in the inner nuclear layer (INL). Next, they used the colocalization technique to demonstrate that melanopsin, a marker of ipRGCs7 and using mouse reporter lines, that TRPM8 expressing cells are indeed expressed in a subset of ipRGCs cells. Furthermore, they showed that TRPM8 is also expressed in cholinergic amacrine cells, characterized by releasing two neurotransmitters, GABA and acetylcholine. Injection of the fluorescent anterograde tracer cholera toxin subunit B (CTB594) into both eyes in two TRPM8 reporter lines indicates the existence of ipRGCs expressing TRPM8 and projecting to the SCN (Figure 1). The choroid is an essential high blood flow vascular structure in the eye and is known to regulate ocular and retinal temperature8 and is richly innervated by sensory trigeminal nerve fibers; therefore, the authors next examined the role of TRPM8 in regulation of eye temperature (Teye) using infrared (IR) thermography. Interestingly, they discovered mice lacking TRPM8 started to decline at temperatures below 25°C, and Trpm8−/− mice displayed a significantly lower Teye than WT littermates when the temperature plate was around 15°C. This suggests a function of TRPM8 and ambient temperature in regulating choroid and ciliary body blood flow and, therefore, in controlling internal ocular temperature. The ability of mice to regulate homeostatic temperature control and the expression of TRPM8 in the ipRGCs is indicative but does not directly link that to central clock regulation. The authors performed expression and functional studies to investigate a direct link between TRPM8 and circadian clockwork at the SCN. First, they determined the expression of the Per2 gene, which is one of the essential components of core circadian clocks in the SCN.9 Authors found in the TRPM8 deficient mouse SCN a significant}, journal={ACTA PHYSIOLOGICA}, author={Mishra, Santosh K. and Gaddameedhi, Shobhan}, year={2023}, month={Jan} }
 @article{zhang_zhang_porter_dakup_wang_robertson_gaddameedhi_zhu_2023, title={Telomere dysfunction in Tert knockout mice delays Braf<SUP>V600E</SUP>-induced melanoma development}, volume={9}, ISSN={["1097-0215"]}, DOI={10.1002/ijc.34713}, abstractNote={Abstract}, journal={INTERNATIONAL JOURNAL OF CANCER}, author={Zhang, Jinglong and Zhang, Fan and Porter, Kenneth I. and Dakup, Panshak P. and Wang, Shuwen and Robertson, Gavin P. and Gaddameedhi, Shobhan and Zhu, Jiyue}, year={2023}, month={Sep} }
 @article{koritala_dakup_porter_gaddameedhi_2023, title={The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study}, url={https://doi.org/10.12688/f1000research.136998.1}, DOI={10.12688/f1000research.136998.1}, abstractNote={Background: The natural day-night cycle synchronizes our circadian rhythms, but modern work practices like night shifts disrupt this pattern, leading to increased exposure to nighttime light. This exposure is linked to various health issues. While some studies have explored the effects of night shifts on human circadian rhythms, there is limited research on the consequences of long-term exposure to shift-work light conditions. Rodents can provide valuable insights into these effects. This study aimed to examine how short- or long-term exposure to rotating shifts and chronic jetlag affects the core circadian oscillators in the liver and skin of mammals.}, journal={F1000Research}, author={Koritala, Bala S. C. and Dakup, Panshak P. and Porter, Kenneth I. and Gaddameedhi, Shobhan}, year={2023}, month={Jun} }
 @article{koritala_dakup_porter_gaddameedhi_2023, title={The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study}, url={https://doi.org/10.12688/f1000research.136998.3}, DOI={10.12688/f1000research.136998.3}, abstractNote={Background: The natural day-night cycle synchronizes our circadian rhythms, but modern work practices like night shifts disrupt this pattern, leading to increased exposure to nighttime light. This exposure is linked to various health issues. While some studies have explored the effects of night shifts on human circadian rhythms, there is limited research on the consequences of long-term exposure to shift-work light conditions. Rodents can provide valuable insights into these effects. This study aimed to examine how short- or long-term exposure to rotating shifts and chronic jetlag affects the core circadian oscillators in the liver and skin of mammals.}, journal={F1000Research}, author={Koritala, Bala S. C. and Dakup, Panshak P. and Porter, Kenneth I. and Gaddameedhi, Shobhan}, year={2023}, month={Aug} }
 @article{koritala_dakup_porter_gaddameedhi_p._koritala_2023, title={The impact of shift-work light conditions on tissue-specific circadian rhythms of canonical clock genes: insights from a mouse model study [version 1; peer review: 1 approved, 1 approved with reservations]}, url={https://f1000research.com/articles/12-762/v1}, DOI={10.12688/f1000research.136998.2}, abstractNote={Background: The natural day-night cycle synchronizes our circadian rhythms, but modern work practices like night shifts disrupt this pattern, leading to increased exposure to nighttime light. This exposure is linked to various health issues. While some studies have explored the effects of night shifts on human circadian rhythms, there is limited research on the consequences of long-term exposure to shift-work light conditions. Rodents can provide valuable insights into these effects. This study aimed to examine how short- or long-term exposure to rotating shifts and chronic jetlag affects the core circadian oscillators in the liver and skin of mammals.}, note={peer review: 1 approved, 1 approved with reservations] F1000Research 2023, 12:762 (https://doi.org/10.12688/f1000research.136998.1}, journal={F1000Research}, author={Koritala, Bala S. C. and Dakup, Panshak P. and Porter, Kenneth I. and Gaddameedhi, Shobhan and P., Dakup Panshak and Koritala, Bala S. C.}, editor={P., Dakup Panshak and Shobhan, Gaddameedhi and Koritala, Bala S. C. and Porter, Kenneth I.Editors}, year={2023}, month={Jun} }
 @article{circadian dysregulation of human dna repair genes and elevated dna damage in simulated night shift schedule_2022, url={https://publons.com/wos-op/publon/54906417/}, journal={Sleep}, year={2022} }
 @article{koritala_porter_sarkar_gaddameedhi_2022, title={Circadian disruption and cisplatin chronotherapy for mammary carcinoma}, volume={436}, ISSN={["1096-0333"]}, url={https://publons.com/wos-op/publon/50851286/}, DOI={10.1016/j.taap.2022.115863}, abstractNote={Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Under normal and disrupted clock conditions, triple-negative mammary carcinoma cells were injected subcutaneously into eight-week-old NOD.Cg-Prkdcscid/J female mice. Tumor volumes and body weights were measured in these mice before and after treatment with cisplatin. We observed an increase in tumor volumes in mice housed under disrupted clock compared to the normal clock conditions. After treatment with cisplatin, we observed a reduced tumor growth rate in mice treated at ZT10 compared to ZT22 and untreated cohorts under normal clock conditions. However, these changes were not seen with the jet-lag protocol. We also observed greater body weight loss in mice treated with ZT10 compared to ZT22 or untreated mice in the jet-lag protocol. Our observations suggest that the effectiveness of cisplatin in mammary carcinoma treatment is time-dependent in the presence of the circadian clock.}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Koritala, Bala S. C. and Porter, Kenneth I. and Sarkar, Soumyadeep and Gaddameedhi, Shobhan}, year={2022}, month={Feb} }
 @article{goodenow_greer_cone_gaddameedhi_2022, title={Circadian effects on UV-induced damage and mutations}, volume={789}, ISSN={["1388-2139"]}, url={https://publons.com/wos-op/publon/54906418/}, DOI={10.1016/j.mrrev.2022.108413}, abstractNote={Skin cancer is the most diagnosed type of cancer in the United States, and while most of these malignancies are highly treatable, treatment costs still exceed $8 billion annually. Over the last 50 years, the annual incidence of skin cancer has steadily grown; therefore, understanding the environmental factors driving these types of cancer is a prominent research-focus. A causality between ultraviolet radiation (UVR) exposure and skin cancer is well-established, but exposure to UVR alone is not necessarily sufficient to induce carcinogenesis. The emerging field of circadian biology intersects strongly with the physiological systems of the mammalian body and introduces a unique opportunity for analyzing mechanisms of homeostatic disruption. The circadian clock refers to the approximate 24-hour cycle, in which protein levels of specific clock-controlled genes (CCGs) fluctuate based on the time of day. Though these CCGs are tissue specific, the skin has been observed to have a robust circadian clock that plays a role in its response to UVR exposure. This in-depth review will detail the mechanisms of the circadian clock and its role in cellular homeostasis. Next, the skin's response to UVR exposure and its induction of DNA damage and mutations will be covered - with an additional focus placed on how the circadian clock influences this response through nucleotide excision repair. Lastly, this review will discuss current models for studying UVR-induced skin lesions and perturbations of the circadian clock, as well as the impact of these factors on human health.}, journal={MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH}, author={Goodenow, Donna and Greer, Adam J. and Cone, Sean J. and Gaddameedhi, Shobhan}, year={2022} }
 @article{kelly_yuen_satterfield_auchus_gaddameedhi_van dongen_liu_2022, title={Endogenous Diurnal Patterns of Adrenal and Gonadal Hormones During a 24-Hour Constant Routine After Simulated Shift Work}, volume={6}, ISSN={["2472-1972"]}, DOI={10.1210/jendso/bvac153}, abstractNote={Abstract}, number={12}, journal={JOURNAL OF THE ENDOCRINE SOCIETY}, author={Kelly, Monica R. and Yuen, Fiona and Satterfield, Brieann C. and Auchus, Richard J. and Gaddameedhi, Shobhan and Van Dongen, Hans P. A. and Liu, Peter Y.}, year={2022}, month={Oct} }
 @article{dakup_greer_gaddameedhi_2022, title={Let's talk about sex: A biological variable in immune response against melanoma}, volume={35}, ISSN={["1755-148X"]}, url={https://doi.org/10.1111/pcmr.13028}, DOI={10.1111/pcmr.13028}, abstractNote={Abstract}, number={2}, journal={PIGMENT CELL & MELANOMA RESEARCH}, publisher={Wiley}, author={Dakup, Panshak P. and Greer, Adam J. and Gaddameedhi, Shobhan}, year={2022}, month={Feb} }
 @article{kyle_bramer_claborne_stratton_bloodsworth_teeguarden_gaddameedhi_metz_van dongen_2022, title={Simulated Night- Shift Schedule Disrupts the Plasma Lipidome and Reveals Early Markers of Cardiovascular Disease Risk}, volume={14}, ISSN={["1179-1608"]}, url={https://publons.com/wos-op/publon/53707085/}, DOI={10.2147/NSS.S363437}, abstractNote={Introduction The circadian system coordinates daily rhythms in lipid metabolism, storage and utilization. Disruptions of internal circadian rhythms due to altered sleep/wake schedules, such as in night-shift work, have been implicated in increased risk of cardiovascular disease and metabolic disorders. To determine the impact of a night-shift schedule on the human blood plasma lipidome, an in-laboratory simulated shift work study was conducted. Methods Fourteen healthy young adults were assigned to 3 days of either a simulated day or night-shift schedule, followed by a 24-h constant routine protocol with fixed environmental conditions, hourly isocaloric snacks, and constant wakefulness to investigate endogenous circadian rhythms. Blood plasma samples collected at 3-h intervals were subjected to untargeted lipidomics analysis. Results More than 400 lipids were identified and quantified across 21 subclasses. Focusing on lipids with low between-subject variation per shift condition, alterations in the circulating plasma lipidome revealed generally increased mean triglyceride levels and decreased mean phospholipid levels after night-shift relative to day-shift. The circadian rhythms of triglycerides containing odd chain fatty acids peaked earlier during constant routine after night-shift. Regardless of shift condition, triglycerides tended to either peak or be depleted at 16:30 h, with chain-specific differences associated with the direction of change. Discussion The simulated night-shift schedule was associated with altered temporal patterns in the lipidome. This may be premorbid to the elevated cardiovascular risk that has been found epidemiologically in night-shift workers.}, journal={NATURE AND SCIENCE OF SLEEP}, author={Kyle, Jennifer E. and Bramer, Lisa M. and Claborne, Daniel and Stratton, Kelly G. and Bloodsworth, Kent J. and Teeguarden, Justin G. and Gaddameedhi, Shobhan and Metz, Thomas O. and Van Dongen, Hans P. A.}, year={2022}, pages={981–994} }
 @article{muck_hudson_honn_gaddameedhi_van dongen_2022, title={Working around the Clock: Is a Person's Endogenous Circadian Timing for Optimal Neurobehavioral Functioning Inherently Task-Dependent?}, volume={4}, ISSN={["2624-5175"]}, url={https://publons.com/wos-op/publon/53707084/}, DOI={10.3390/clockssleep4010005}, abstractNote={Neurobehavioral task performance is modulated by the circadian and homeostatic processes of sleep/wake regulation. Biomathematical modeling of the temporal dynamics of these processes and their interaction allows for prospective prediction of performance impairment in shift-workers and provides a basis for fatigue risk management in 24/7 operations. It has been reported, however, that the impact of the circadian rhythm—and in particular its timing—is inherently task-dependent, which would have profound implications for our understanding of the temporal dynamics of neurobehavioral functioning and the accuracy of biomathematical model predictions. We investigated this issue in a laboratory study designed to unambiguously dissociate the influences of the circadian and homeostatic processes on neurobehavioral performance, as measured during a constant routine protocol preceded by three days on either a simulated night shift or a simulated day shift schedule. Neurobehavioral functions were measured every 2 h using three functionally distinct assays: a digit symbol substitution test, a psychomotor vigilance test, and the Karolinska Sleepiness Scale. After dissociating the circadian and homeostatic influences and accounting for inter-individual variability, peak circadian performance occurred in the late biological afternoon (in the “wake maintenance zone”) for all three neurobehavioral assays. Our results are incongruent with the idea of inherent task-dependent differences in the endogenous circadian impact on performance. Rather, our results suggest that neurobehavioral functions are under top-down circadian control, consistent with the way they are accounted for in extant biomathematical models.}, number={1}, journal={CLOCKS & SLEEP}, author={Muck, Rachael A. and Hudson, Amanda N. and Honn, Kimberly A. and Gaddameedhi, Shobhan and Van Dongen, Hans P. A.}, year={2022}, month={Mar}, pages={23–36} }
 @article{sarkar_porter_dakup_gajula_koritala_hylton_kemp_wakamatsu_gaddameedhi_2021, title={Circadian clock protein BMAL1 regulates melanogenesis through MITF in melanoma cells}, volume={34}, ISSN={["1755-148X"]}, url={https://doi.org/10.1111/pcmr.12998}, DOI={10.1111/pcmr.12998}, abstractNote={Abstract}, number={5}, journal={PIGMENT CELL & MELANOMA RESEARCH}, publisher={Wiley}, author={Sarkar, Soumyadeep and Porter, Kenneth I and Dakup, Panshak P. and Gajula, Rajendra P. and Koritala, Bala S. C. and Hylton, Ryan and Kemp, Michael G. and Wakamatsu, Kazumasa and Gaddameedhi, Shobhan}, year={2021}, month={Jul} }
 @article{hayter_wehrens_van dongen_stangherlin_gaddameedhi_crooks_barron_venetucci_o' neill_brown_et al._2021, title={Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia}, volume={12}, ISSN={["2041-1723"]}, url={https://publons.com/wos-op/publon/45758593/}, DOI={10.1038/s41467-021-22788-8}, abstractNote={Abstract}, number={1}, journal={NATURE COMMUNICATIONS}, author={Hayter, Edward A. and Wehrens, Sophie M. T. and Van Dongen, Hans P. A. and Stangherlin, Alessandra and Gaddameedhi, Shobhan and Crooks, Elena and Barron, Nichola J. and Venetucci, Luigi A. and O' Neill, John S. and Brown, Timothy M. and et al.}, year={2021}, month={Apr} }
 @article{liu_irwin_krueger_gaddameedhi_dongen_2021, title={Night shift schedule alters endogenous regulation of circulating cytokines}, volume={10}, url={https://doi.org/10.1016/j.nbscr.2021.100063}, DOI={10.1016/j.nbscr.2021.100063}, abstractNote={Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true endogenous pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t13 = -6.03, p < 0.001), without any significant differences in IL-1β, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t13 = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).}, journal={Neurobiology of Sleep and Circadian Rhythms}, publisher={Elsevier BV}, author={Liu, Peter Y. and Irwin, Michael R. and Krueger, James M. and Gaddameedhi, Shobhan and Dongen, Hans P.A. Van}, year={2021}, month={May}, pages={100063} }
 @article{koritala_porter_arshad_gajula_mitchell_arman_manjanatha_teeguarden_van dongen_mcdermott_et al._2021, title={Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans}, volume={70}, ISSN={["1600-079X"]}, url={https://publons.com/wos-op/publon/35185561/}, DOI={10.1111/jpi.12726}, abstractNote={Abstract}, number={3}, journal={JOURNAL OF PINEAL RESEARCH}, author={Koritala, Bala S. C. and Porter, Kenneth I. and Arshad, Osama A. and Gajula, Rajendra P. and Mitchell, Hugh D. and Arman, Tarana and Manjanatha, Mugimane G. and Teeguarden, Justin and Van Dongen, Hans P. A. and McDermott, Jason E. and et al.}, year={2021}, month={Apr} }
 @article{xu_cheng_zhao_zhang_zhu_zhang_chen_wang_yan_robertson_et al._2021, title={Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene}, volume={118}, ISSN={["0027-8424"]}, url={https://publons.com/wos-op/publon/47740196/}, DOI={10.1073/pnas.2019043118}, abstractNote={Significance}, number={26}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Xu, Tao and Cheng, De and Zhao, Yuanjun and Zhang, Jinglong and Zhu, Xiaolu and Zhang, Fan and Chen, Gang and Wang, Yang and Yan, Xiufeng and Robertson, Gavin P. and et al.}, year={2021}, month={Jun} }
 @article{khalyfa_gaddameedhi_crooks_zhang_li_qiao_trzepizur_kay_andrade_satterfield_et al._2020, title={Circulating Exosomal miRNAs Signal Circadian Misalignment to Peripheral Metabolic Tissues}, volume={21}, ISSN={["1422-0067"]}, url={https://publons.com/wos-op/publon/33435120/}, DOI={10.3390/ijms21176396}, abstractNote={Night shift work increases risk of metabolic disorders, particularly obesity and insulin resistance. While the underlying mechanisms are unknown, evidence points to misalignment of peripheral oscillators causing metabolic disturbances. A pathway conveying such misalignment may involve exosome-based intercellular communication. Fourteen volunteers were assigned to a simulated day shift (DS) or night shift (NS) condition. After 3 days on the simulated shift schedule, blood samples were collected during a 24-h constant routine protocol. Exosomes were isolated from the plasma samples from each of the blood draws. Exosomes were added to naïve differentiated adipocytes, and insulin-induced pAkt/Akt expression changes were assessed. ChIP-Seq analyses for BMAL1 protein, mRNA microarrays and exosomal miRNA arrays combined with bioinformatics and functional effects of agomirs and antagomirs targeting miRNAs in NS and DS exosomal cargo were examined. Human adipocytes treated with exosomes from the NS condition showed altered Akt phosphorylation responses to insulin in comparison to those treated with exosomes from the DS condition. BMAL1 ChIP-Seq of exosome-treated adipocytes showed 42,037 binding sites in the DS condition and 5538 sites in the NS condition, with a large proportion of BMAL1 targets including genes encoding for metabolic regulators. A significant and restricted miRNA exosomal signature emerged after exposure to the NS condition. Among the exosomal miRNAs regulated differentially after 3 days of simulated NS versus DS, proof-of-concept validation of circadian misalignment signaling was demonstrated with hsa-mir-3614-5p. Exosomes from the NS condition markedly altered expression of key genes related to circadian rhythm in several cultured cell types, including adipocytes, myocytes, and hepatocytes, along with significant changes in 29 genes and downstream gene network interactions. Our results indicate that a simulated NS schedule leads to changes in exosomal cargo in the circulation. These changes promote reduction of insulin sensitivity of adipocytes in vitro and alter the expression of core clock genes in peripheral tissues. Circulating exosomal miRNAs may play an important role in metabolic dysfunction in NS workers by serving as messengers of circadian misalignment to peripheral tissues.}, number={17}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Khalyfa, Abdelnaby and Gaddameedhi, Shobhan and Crooks, Elena and Zhang, Chunling and Li, Yan and Qiao, Zhuanhong and Trzepizur, Wojciech and Kay, Steve A. and Andrade, Jorge and Satterfield, Brieann C. and et al.}, year={2020}, month={Sep} }
 @article{dakup_porter_little_zhang_gaddameedhi_2020, title={Sex differences in the association between tumor growth and T cell response in a melanoma mouse model}, volume={69}, url={https://doi.org/10.1007/s00262-020-02643-3}, DOI={10.1007/s00262-020-02643-3}, abstractNote={Epidemiological evidence suggests that females have an advantage over males in cases of melanoma incidence, progression, and survival. However, the biological mechanisms underlying these sex differences remain unclear. With the knowledge that females generally have a more robust immune system than males, we investigated sex differences in melanoma progression in a B16-F10/BL6 syngeneic mouse model. We observed significantly less tumor volume and growth rate over 14 days in female mice compared to male mice. Furthermore, higher populations of CD4+ and CD8+ T cells, which indicate adaptive immune responses, were found in the circulating blood and tumors of females and corresponded with less tumor growth, and vice versa in males. Our results highlight a mouse model that represents melanoma progression in the human population and displays a higher immune response to melanoma in females compared to males. These findings suggest that the immune system may be one of the mechanisms responsible for sex differences in melanoma.}, number={10}, journal={Cancer Immunology, Immunotherapy}, publisher={Springer Science and Business Media LLC}, author={Dakup, Panshak P. and Porter, Kenneth I. and Little, Alexander A. and Zhang, Hui and Gaddameedhi, Shobhan}, year={2020}, month={Oct}, pages={2157–2162} }
 @article{solar ultraviolet-induced dna damage response: melanocytes story in transformation to environmental melanomagenesis._2020, url={https://doi.org/10.1002/em.22370}, DOI={10.1002/em.22370}, abstractNote={Abstract}, journal={Environmental and molecular mutagenesis}, year={2020}, month={May} }
 @article{dakup_porter_gaddameedhi_2020, title={The circadian clock protects against acute radiation-induced dermatitis}, volume={399}, url={https://doi.org/10.1016/j.taap.2020.115040}, DOI={10.1016/j.taap.2020.115040}, abstractNote={Radiation-induced dermatitis is a common occurrence in cancer patients undergoing radiation therapy (RT) and is caused when ionizing radiation (IR) induces DNA strand breaks in skin cells. The wide use of RT in cancer treatments makes it important to minimize RT-induced toxicities including radiodermatitis. This study sought to determine if the circadian clock plays a protective role in minimizing radiodermatitis. We treated mice in control (Day Shift), environmentally-disrupted (Rotating Shift) and genetically-disrupted (Per 1/2−/−) circadian conditions with 6 Gy of IR to the whole body. There was a significantly increased number of radiodermatitis spots on mice with circadian clock disruption compared to control mice. Additionally, circadian clock disrupted mice exhibited reduced protein levels of Bmal1, a phenomenon that sensitized circadian synchronized keratinocytes to IR-induced DNA damage. Furthermore, the skin phenotype results corresponded with significantly reduced body weights and increased genomic DNA damage in blood cells of mice with clock disruption compared to control mice. These findings suggest that the circadian clock plays a protective role in IR-induced DNA damage and skin toxicity, possibly through BMAL1-dependent mechanisms, and potentially impacts RT-associated radiodermatitis in cancer patients.}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Dakup, Panshak P. and Porter, Kenneth I. and Gaddameedhi, Shobhan}, year={2020}, month={Jul}, pages={115040} }
 @article{the circadian clock protects against ionizing radiation-induced cardiotoxicity._2020, url={https://doi.org/10.1096/fj.201901850RR}, DOI={10.1096/fj.201901850rr}, abstractNote={Radiation therapy (RT) is commonly used to treat solid tumors of the breast, lung, and esophagus; however, the heart is an unintentional target of ionizing radiation (IR). IR exposure to the heart results in chronic toxicities including heart failure. We hypothesize that the circadian system plays regulatory roles in minimizing the IR‐induced cardiotoxicity. We treated mice in control (Day Shift), environmentally disrupted (Rotating Shift), and genetically disrupted (Per 1/2 mutant) circadian conditions with 18 Gy of IR to the heart. Compared to control mice, circadian clock disruption significantly exacerbated post‐IR systolic dysfunction (by ultrasound echocardiography) and increased fibrosis in mice. At the cellular level, Bmal1 protein bound to Atm, Brca1, and Brca2 promoter regions and its expression level was inversely correlated with the DNA damage levels based on the state of the clock. Further studies with circadian synchronized cardiomyocytes revealed that Bmal1 depletion increased the IR‐induced DNA damage and apoptosis. Collectively, these findings suggest that the circadian clock protects from IR‐induced toxicity and potentially impacts RT treatment outcome in cancer patients through IR‐induced DNA damage responses.}, journal={FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, year={2020}, month={Jan} }
 @article{cardiac autonomic activity during simulated shift work_2019, url={https://publons.com/wos-op/publon/32745708/}, DOI={10.2486/INDHEALTH.2018-0044}, abstractNote={Shift work leads to adverse health outcomes including increased risk of cardiovascular disease. Heart rate (HR) and heart rate variability (HRV) are measures of cardiac autonomic activity and markers of cardiovascular disease and mortality. To investigate the effects of shift work on cardiac autonomic activity, we assessed the influence of simulated night work on HR and HRV, and dissociated the direct effects of circadian misalignment from those of sleep displacement and altered physical activity patterns. A total of 29 subjects each participated in one of two in-laboratory, simulated shift work studies. In both studies, EKG was continuously monitored via Holter monitors to measure HR and the high frequency (HF) component of HRV (HF-HRV). We found endogenous circadian rhythmicity in HR and HF-HRV. Sleep and waking physical activity, both displaced during simulated night work, had more substantial, and opposite, effects on HR and HF-HRV. Our findings show systematic but complex, interacting effects of time of day, sleep/wake state, and physical activity on cardiac autonomic activity. These effects need to be taken into account when evaluating HR and HRV in shift work settings and when interpreting these measures of cardiac autonomic activity as markers of cardiovascular disease.}, journal={Industrial Health}, year={2019} }
 @article{it's about time: advances in understanding the circadian regulation of dna damage and repair in carcinogenesis and cancer treatment outcomes_2019, url={https://publons.com/wos-op/publon/32413204/}, journal={Yale Journal of Biology and Medicine}, year={2019} }
 @article{it's about time: advances in understanding the circadian regulation of dna damage and repair in carcinogenesis and cancer treatment outcomes._2019, url={https://europepmc.org/articles/PMC6585512}, journal={The Yale journal of biology and medicine}, year={2019}, month={Jun} }
 @article{circadian clock protects against radiation-induced dermatitis and cardiomyopathy in mice_2018, url={https://publons.com/wos-op/publon/32413206/}, DOI={10.1158/1538-7445.AM2018-4159}, abstractNote={Abstract}, journal={Cancer Research}, year={2018} }
 @article{circulating plasma exosomes may signal circadian clock misalignment to peripheral tissues_2018, url={https://publons.com/wos-op/publon/35726971/}, journal={American Journal of Respiratory and Critical Care Medicine}, year={2018} }
 @article{skene_skornyakov_chowdhury_gajula_middleton_satterfield_porter_dongen_gaddameedhi_2018, title={Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism}, volume={115}, url={https://doi.org/10.1073/pnas.1801183115}, DOI={10.1073/pnas.1801183115}, abstractNote={Significance}, number={30}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Skene, Debra J. and Skornyakov, Elena and Chowdhury, Namrata R. and Gajula, Rajendra P. and Middleton, Benita and Satterfield, Brieann C. and Porter, Kenneth I. and Dongen, Hans P. A. Van and Gaddameedhi, Shobhan}, year={2018}, month={Jul}, pages={7825–7830} }
 @article{the circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models._2018, url={https://europepmc.org/articles/PMC5865687}, DOI={10.18632/oncotarget.24539}, abstractNote={Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2−/− mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2−/− clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2−/− mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.}, journal={Oncotarget}, year={2018}, month={Feb} }
 @article{uv-b-induced erythema in human skin: the circadian clock is ticking._2018, url={https://doi.org/10.1016/j.jid.2017.09.002}, DOI={10.1016/j.jid.2017.09.002}, abstractNote={Acute exposure of skin to UV-B causes DNA damage and sunburn erythema in both mice and humans. Previous studies documented time-of-day-related differences in sunburn responses after UV-B exposure in mice. Because humans are diurnal and mice are nocturnal, the circadian rhythm in human skin was hypothesized to be in opposite phase to the rhythm in mice. A study by Nikkola et al. demonstrates that humans are more prone to sunburn erythema after evening exposure to solar UV-B radiation as compared with morning exposure. Acute exposure of skin to UV-B causes DNA damage and sunburn erythema in both mice and humans. Previous studies documented time-of-day-related differences in sunburn responses after UV-B exposure in mice. Because humans are diurnal and mice are nocturnal, the circadian rhythm in human skin was hypothesized to be in opposite phase to the rhythm in mice. A study by Nikkola et al. demonstrates that humans are more prone to sunburn erythema after evening exposure to solar UV-B radiation as compared with morning exposure. Because mice are nocturnal and humans are diurnal, their circadian clock outputs are out of phase. Based on this argument, and previous data relating time-of-day UV exposure to severity of UV effects in mouse skin, it was proposed that humans would be more prone to sunburn after late afternoon UV exposure rather than morning exposure.The majority of living organisms on the Earth are photosensitive and are influenced by the solar day and night cycle created by the axial rotation of the Earth. Consequently, cells have developed an amazing time-keeping mechanism known as the circadian clock that is self-sustained and oscillates with a periodic cycle of approximately 24 hours. In mammals, the molecular clock is entrained daily by the morning sunlight entering the eyes to reset the master clock located in the suprachiasmatic nucleus of the brain. The suprachiasmatic nucleus, via various hormonal and neuronal signals, synchronizes peripheral tissues including the heart, lung, liver, and skin. At the molecular level, the circadian clock is made up of primary as well as secondary feedback loops that are primarily responsible for approximately 24-hour rhythmicity of clock-controlled genes. Proteins including brain and muscle ARNT-like protein 1 (BMAL1), circadian locomotor output kaput (CLOCK), cryptochromes (CRY 1, 2), and periods (PER 1, 2, 3) make up a transcriptional-translational feedback loop that is initiated by dimerization of BMAL1 and CLOCK and the subsequent binding of this complex to the E-Box sequence (CACGTG or CACGTT) found in the promoter region of target clock-controlled genes (Lowrey and Takahashi, 2011Lowrey P.L. Takahashi J.S. Genetics of circadian rhythms in Mammalian model organisms.Adv Genet. 2011; 74: 175-230Crossref PubMed Scopus (409) Google Scholar). Tissue-specific circadian expression patterns have been observed in as many as 10% of mammalian genes, and many of these genes regulate cell cycle, metabolism, cell death, and DNA repair processes (Sancar et al., 2015Sancar A. Lindsey-Boltz L.A. Gaddameedhi S. Selby C.P. Ye R. Chiou Y.Y. et al.Circadian clock, cancer, and chemotherapy.Biochemistry. 2015; 54: 110-123Crossref PubMed Scopus (109) Google Scholar). Because mice are nocturnal and humans are diurnal, their circadian clock outputs are out of phase. Based on this argument, and previous data relating time-of-day UV exposure to severity of UV effects in mouse skin, it was proposed that humans would be more prone to sunburn after late afternoon UV exposure rather than morning exposure. Apart from its life-giving quality, the Sun emits harmful UVR that induces DNA damage in skin. Exposure to UVR causes a plethora of skin-related issues including photoaging, sunburn erythema, and skin cancers including melanomas, the deadliest skin cancers. In recent years, the skin’s circadian clock has been shown to regulate various cellular responses after UVR exposure, including nucleotide excision repair, cell cycle checkpoints, oxidative stress, and apoptosis (Dakup and Gaddameedhi, 2017Dakup P. Gaddameedhi S. Impact of the circadian clock on UV-induced DNA damage response and photocarcinogenesis.Photochem Photobiol. 2017; 93: 296-303Crossref PubMed Scopus (37) Google Scholar, Gaddameedhi et al., 2011Gaddameedhi S. Selby C.P. Kaufmann W.K. Smart R.C. Sancar A. Control of skin cancer by the circadian rhythm.Proc Natl Acad Sci USA. 2011; 108: 18790-18795Crossref PubMed Scopus (163) Google Scholar, Geyfman et al., 2012Geyfman M. Kumar V. Liu Q. Ruiz R. Gordon W. Espitia F. et al.Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis.Proc Natl Acad Sci USA. 2012; 109: 11758-11763Crossref PubMed Scopus (162) Google Scholar, Plikus et al., 2015Plikus M.V. Van Spyk E.N. Pham K. Geyfman M. Kumar V. Takahashi J.S. et al.The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity.J Biol Rhythms. 2015; 30: 163-182Crossref PubMed Scopus (103) Google Scholar, Sancar et al., 2015Sancar A. Lindsey-Boltz L.A. Gaddameedhi S. Selby C.P. Ye R. Chiou Y.Y. et al.Circadian clock, cancer, and chemotherapy.Biochemistry. 2015; 54: 110-123Crossref PubMed Scopus (109) Google Scholar, Wang et al., 2017Wang H. van Spyk E. Liu Q. Geyfman M. Salmans M.L. Kumar V. et al.Time-restricted feeding shifts the skin circadian clock and alters UVB-induced DNA damage.Cell Rep. 2017; 20: 1061-1072Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). These robust protective mechanisms attenuate unwanted consequences of UVR-mediated DNA damage. Skin clock regulation of nucleotide excision repair has been well characterized using the SKH-1 hairless mouse model, where it was observed that an elevated rate of UV photoproduct removal correlated with higher expression of the core nucleotide excision repair factor Xpa in the evening as compared with the morning (Gaddameedhi et al., 2011Gaddameedhi S. Selby C.P. Kaufmann W.K. Smart R.C. Sancar A. Control of skin cancer by the circadian rhythm.Proc Natl Acad Sci USA. 2011; 108: 18790-18795Crossref PubMed Scopus (163) Google Scholar). However, acute exposure to UVR also causes a UV-induced inflammatory reaction that is characterized by vasodilation and increased blood flow to the dermis, resulting in sunburn erythema in the affected skin. Using SKH-1 hairless mice, we have shown that more sunburn erythema occurs in morning solar UV-B-treated mice than in evening-treated animals (Gaddameedhi et al., 2015Gaddameedhi S. Selby C.P. Kemp M.G. Ye R. Sancar A. The circadian clock controls sunburn apoptosis and erythema in mouse skin.J Invest Dermatol. 2015; 135: 1119-1127Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). We determined that during morning time, when DNA repair is lowest and DNA synthesis is highest, the DNA damage caused by UVR leads to stronger activation of the Atr protein kinase, which is known to be activated in response to replication stress and to regulate the stability of the tumor suppressor p53. This results in increased numbers of sunburn apoptotic cells and enhanced inflammation in mouse skin. Because mice are nocturnal and humans are diurnal, their circadian clock outputs are out of phase. Based on this argument, and previous data relating time-of-day UV exposure to severity of UV effects in mouse skin, it was proposed that humans would be more prone to sunburn after late afternoon UV exposure rather than morning exposure. Nikkola et al. evaluated the circadian time effect of narrow band-UV-B exposure on sunburn erythema in human skin. They selected 19 subjects (16 females and 3 males) having skin types II and III as defined by Fitzpatrick sun-reactive skin type scale (Fitzpatrick, 1988Fitzpatrick T.B. The validity and practicality of sun-reactive skin types I through VI.Arch Dermatol. 1988; 124: 869-871Crossref PubMed Scopus (3021) Google Scholar). Subjects were exposed to increasing doses of narrow band-UV-B up to 4 suberythemal dose, once in the morning between 7 am and 9 am on one buttock and once in the evening between 7 pm and 9 pm on the other buttock of the same subject. Twenty-four hours after UV-B treatment, the erythema of the skin patches was quantified and skin biopsies were irradiated with the highest dose of UV-B (i.e., 4 suberythemal dose = 40 mJ/cm2 CIE (Commission Internationale de l'Eclairage, Vienna, Austria)) were collected. Protein levels of the tumor suppressor proteins p53 and the clock proteins CRY1 and CRY2 were measured in biopsies. Interestingly, the authors found that human subjects treated with UV-B in the evening had a significantly higher erythema index scores in comparison with the subjects exposed in the morning. In addition, different levels of CRY1 and CRY2 were detected in irradiated skin using immunohistochemistry, and human subjects with a negligible amount of CRY2 showed more erythema relative to individuals with high levels of CRY2. This is a novel observation. The authors speculated that CRY2 protects against UV-B-mediated skin damage. In a different study, the Lamia group reported that CRY2 regulated c-MYC proteasomal degradation by acting as a cofactor for the SCF substrate adaptor FBXL3 (an E3 ligase protein) (Huber et al., 2016Huber A.L. Papp S.J. Chan A.B. Henriksson E. Jordan S.D. Kriebs A. et al.CRY2 and FBXL3 cooperatively degrade c-MYC.Mol Cell. 2016; 64: 774-789Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Because c-MYC plays important roles in cell proliferation, cell growth, and apoptosis, high levels of CRY2 could enhance c-MYC degradation, which in turn might reduce sunburn-induced apoptosis and other characteristic features of sunburn erythema. It would be interesting to evaluate levels of core clock proteins including CRY1, 2, PER1, 2, 3, BMAL1, and CLOCK in a larger sample set. Also, knowing the chronotype (behavioral manifestation of the underlying biological clock) of the patients with negligible amount of CRY2 levels would facilitate understanding the effects of circadian clock disruption on sunburn erythema. Collectively, the above additional information would define mechanistic similarities and circadian phase output differences between human and mouse models as shown in Figure 1. In addition to CRY protein levels, Nikkola et al. also measured p53 concentrations in skin biopsies and observed increased p53 levels in the morning samples compared with the evening group. This observation appears to contradict the predicted human skin sunburn model, but the authors suggested that the possible reasons for this observation were either delayed (24 hours after UV-B irradiation) biopsy collection in comparison with the mouse study previously conducted by us or a dissociation of human p53 elevation and erythema as previously suggested (Healy et al., 1994Healy E. Reynolds N.J. Smith M.D. Campbell C. Farr P.M. Rees J.L. Dissociation of erythema and p53 protein expression in human skin following UVB irradiation, and induction of p53 protein and mRNA following application of skin irritants.J Invest Dermatol. 1994; 103: 493-499Abstract Full Text PDF PubMed Google Scholar). However, the paper by Healy et al. did not consider the circadian aspect of p53 and erythema, nor were subjects selected according to chronotype. Thus, the observations by Healy et al. may not be directly relatable to the current study. In contrast, strong evidence of p53 involvement in sunburn erythema was shown by Brash’s group using p53 knockout mouse models, where they demonstrated that deleting p53 gene in mouse skin decreased the number of sunburn-mediated apoptotic cells after exposure to UV-B (Ziegler et al., 1994Ziegler A. Jonason A.S. Leffell D.J. Simon J.A. Sharma H.W. Kimmelman J. et al.Sunburn and p53 in the onset of skin cancer.Nature. 1994; 372: 773-776Crossref PubMed Scopus (1348) Google Scholar). In another recent paper (Guan et al., 2016Guan L. Suggs A. Ahsanuddin S. Tarrillion M. Selph J. Lam M. et al.2016 Arte poster competition first place winner: circadian rhythm and UV-induced skin damage: an in vivo study.J Drugs Dermatol. 2016; 15: 1124-1130PubMed Google Scholar) in which erythema induction was examined as a function of time-of-day of UV exposure, the authors reported enhanced erythema in human subjects after morning treatment in comparison with evening exposure. However, this study used solar simulated radiation, which is primarily composed of UV-A radiation that is much less efficient at inducing canonical UV bipyrimidine dimers in DNA, rather than narrow band-UV-B as in the Nikkola et al. study. Guan et al. also did not evaluate core clock gene expression levels in skin biopsies of the subjects, which is important to understand the circadian phase of the observations. In future studies, it will be interesting to determine how different experimental parameters and variables in the Guan et al. and Nikkola et al. studies contribute to the unique time-of-day erythemal responses in humans. It should be noted that there are additional factors that may contribute to circadian effects on UV responses in human skin, such as skin type, sleep cycles, and feeding behaviors of the participating human volunteers. These issues are more difficult to control for in human studies than in mice. In a recent elegant study, the Andersen group showed that restricting feeding to the inactive phase (during day time) in mice shifts the skin’s circadian clock and its response to solar UV-B irradiation (Wang et al., 2017Wang H. van Spyk E. Liu Q. Geyfman M. Salmans M.L. Kumar V. et al.Time-restricted feeding shifts the skin circadian clock and alters UVB-induced DNA damage.Cell Rep. 2017; 20: 1061-1072Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The group concluded that daytime feeding reverses diurnal sensitivity to UVB-induced DNA damage specifically by influencing the oscillatory expression pattern of the Xpa gene. Feeding and social behaviors of human subjects may also affect UV responses and should therefore be considered when designing future studies involving humans. A few possible solutions to this problem include evaluating participating human subjects in sleep research labs, where their sleep cycles, physical activity, and feeding patterns can be closely monitored, or formulating detailed questionnaires for the volunteers at the time of enrollment. Collectively, the Nikkola et al. and Guan et al. papers show involvement of circadian timing in UVR-induced sunburn erythema in humans, but report different observations relating the intensity of sunburn erythema to time-of-day UVR exposure. Observations of core clock gene expression pattern in the −/+UV-B-treated skin samples bolster the involvement of circadian clock regulation in UV-B-induced sunburn erythema in humans. However, it would have been fascinating to perform additional mechanistic studies to understand the signaling events occurring through the skin’s circadian clock on UVR exposure and correlate the results with the observed phenotype in humans. Our environment is constantly changing, challenging us both socially and biologically, and pushing us to adopt erratic time schedules. Irregular and unhealthy sleep cycles and feeding patterns are disrupting our natural circadian rhythm and making us vulnerable to environmental stresses that vary depending on the time-of-day. Despite the strong evidence that the circadian clock impacts on sunburn erythema in mice, there are still active debate about the vulnerability of human skin to UVR-induced erythema as a function of the time-of-day of exposure. One reason for continued controversy could be huge variations in the natural rhythm among humans, which make such studies much more difficult and time consuming. Hence, special efforts should be made to select appropriate human volunteers. Identification of the optimal time-of-day to minimize sunburn erythema in humans may soon be possible, and may be consistent with the model proposed by Gaddameedhi et al., 2015Gaddameedhi S. Selby C.P. Kemp M.G. Ye R. Sancar A. The circadian clock controls sunburn apoptosis and erythema in mouse skin.J Invest Dermatol. 2015; 135: 1119-1127Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar. Until then, minimization of sun exposure and photoprotection should continue to be recommended. The authors state no conflict of interest. The authors thank Dr Michael G. Kemp at Wright State University and Panshak Dakup at WSU for critical reading of this commentary. SG was supported by National Institutes of Health grant 4R00ES022640 and WSU College of Pharmacy. Circadian Time Effects on NB-UVB–Induced Erythema in Human Skin In VivoJournal of Investigative DermatologyVol. 138Issue 2PreviewUVR-induced skin erythema occurs after DNA damage, a consequence of the cell signaling cascades and synthesis of various cytokines and inflammatory mediators detected as vasodilation, inflammation, and apoptosis (Sklar et al., 2013). UVB-induced carcinogenesis has been linked to circadian time in mice, because those subjected to chronic UVB radiation in the morning had a 5-fold higher number of invasive squamous cell carcinomas compared with the evening-treated group (Gaddameedhi et al., 2011). Full-Text PDF Open Archive}, journal={The Journal of investigative dermatology}, year={2018}, month={Feb} }
 @article{chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model_2017, url={https://publons.com/wos-op/publon/32413210/}, DOI={10.1158/1538-7445.AM2017-1120}, abstractNote={Abstract}, journal={Cancer Research}, year={2017} }
 @article{impact of the circadian clock on uv-induced dna damage response and photocarcinogenesis_2017, url={https://publons.com/wos-op/publon/32413211/}, DOI={10.1111/PHP.12662}, abstractNote={Abstract}, journal={Photochemistry & Photobiology}, year={2017} }
 @article{shift work: disrupted circadian rhythms and sleep-implications for health and well-being._2017, url={https://europepmc.org/articles/PMC5647832}, DOI={10.1007/s40675-017-0071-6}, abstractNote={Our 24/7 society is dependent on shift work, despite mounting evidence for negative health outcomes from sleep displacement due to shift work. This paper reviews short- and long-term health consequences of sleep displacement and circadian misalignment due to shift work.We focus on four broad health domains: metabolic health; risk of cancer; cardiovascular health; and mental health. Circadian misalignment affects these domains by inducing sleep deficiency, sympathovagal and hormonal imbalance, inflammation, impaired glucose metabolism, and dysregulated cell cycles. This leads to a range of medical conditions, including obesity, metabolic syndrome, type II diabetes, gastrointestinal dysfunction, compromised immune function, cardiovascular disease, excessive sleepiness, mood and social disorders, and increased cancer risk.Interactions of biological disturbances with behavioral and societal factors shape the effects of shift work on health and well-being. Research is needed to better understand the underlying mechanisms and drive the development of countermeasures.}, journal={Current sleep medicine reports}, year={2017}, month={Apr} }
 @article{chronopharmacology of cisplatin: role of the circadian rhythm in modulating the cisplatin transporters levels_2016, url={https://publons.com/wos-op/publon/32413213/}, journal={The FASEB Journal}, year={2016} }
 @article{circadian clock, cancer, and chemotherapy_2015, url={https://publons.com/wos-op/publon/6089121/}, DOI={10.1021/BI5007354}, abstractNote={The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock–DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs.}, journal={Biochemistry}, year={2015} }
 @article{commentary: chemiexcitation of melanin derivatives induces dna photoproducts long after uv exposure._2015, url={https://europepmc.org/articles/PMC4594339}, DOI={10.3389/fphys.2015.00276}, abstractNote={Cutaneous malignant melanoma (CMM) is one of the most rapidly increasing cancers in the western world (Bowden, 2004). Frequency of its occurrence is closely associated with skin color and depends on geographical zone (Leiter and Garbe, 2008). Multiple epidemiological studies in humans (Whiteman et al., 2007) and experimental studies with mouse melanoma models suggest that sunburn during childhood confers the highest risk of melanoma development later in life (Noonan et al., 2001). Ultraviolet radiation (UVR) from sunlight that reaches earth is comprised of 90–99% UVA (320–400 nm) and 1–10% UVB (280–320 nm), as most UVB is absorbed by stratospheric ozone (Bowden, 2004). High energy UVB is strongly absorbed by epidermal genomic DNA resulting in direct DNA damage by generating two major photoproducts: cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4 PPs), both of which are mutagenic and carcinogenic in animal models as well as in humans (Bowden, 2004; Lima-Bessa and Menck, 2005). These photoproducts are solely repaired by the process of nucleotide excision repair (Sancar et al., 2004) and the loss of this repair system is strongly correlated with increased melanoma. This loss results from transformed melanocytes, while non-melanoma skin cancers originate from malignantly transformed keratinocytes (Kraemer, 1997; Bowden, 2004). Although it was established that melanin that is specifically synthesized within melanocytes protects against direct DNA damage by absorbing the energy from UVR (Sinha and Hader, 2002). Recent findings from two independent research groups suggest that melanin might contribute to additional DNA damage and might further lead to increased risk of skin cancers (Noonan et al., 2012; Premi et al., 2015). 
 
Using hepatocyte growth factor/scatter factor (HGF) transgenic mice with a controlled UVR delivering system on neonatal mice, Noonan et al., have unraveled interesting findings regarding UVA and UVB-induced melanomagenesis (Noonan et al., 2012). In their experiments, 3 day old C57BL/6-HGF (Black and melanin pigmented), C57BL/6-c-HGF tyrosinase mutant (Albino and no melanin pigment) transgenic mice were irradiated with both UVA and UVB, then with specific UVA or UVB at a biological dosage. The authors have found that UV induction of melanin contributes to melanomagenesis only by UVA and not by UVB radiation. This UVA-mediated melanoma development was associated with oxidative DNA damage in melanin containing black mice and not in albino mice from the same genetic background. However, the biochemical explanation for melanin associated oxidative DNA damage in pigmented melanocytes needs to be addressed. 
 
In a recent study, Brash and his colleagues have elegantly demonstrated the mechanistic and biochemical pathways of interaction of melanin and its contribution to UV-mediated DNA damage response. In the process, the authors have discovered a novel mechanism of generating “Dark” CPDs (Premi et al., 2015). It is well documented that CPDs are formed within picoseconds after a UV photon is absorbed at thymine or cytosine sites in DNA (Schreier et al., 2007). For the first time, Brash and his colleagues have shown that CPD production continued even several hours after UVA treatment in melanin containing murine melanocytes. These CPDs, generated at a later time after irradiation, were called “Dark CPDs.” However, this phenomena was absent in murine fibroblasts and albino melanocytes which lack melanin pigment. This suggests that melanin might contribute to increased DNA damage through dark CPDs. Also UVB irradiated pigmented melanocytes generated dark CPDs, which are comparable to UVA. Remarkably UVB-mediated CPD production was highest after 4 h of irradiation, while UVA-mediated CPDs peaked at 2 h. 
 
To further examine the effect of UVA on dark CPD generation in vivo, the authors have used a transgenic mouse model overexpressing Kit ligand (K14-kitl), where melanocytes are localized within the epidermis. UVA exposure of these mice showed CPD generation 3 times higher at 2 hours relative to 0 h post-irradiation. The majority of these were cytosine containing CPDs that are responsible for UV-signature C → T mutations as opposed to TT CPDs, which are most typical of cells irradiated with UVR. Further in response to UVA irradiation, melanin generates reactive oxygen species like superoxide's (O2-·). Additionally UVA rapidly induces NADPH oxidase (NOX) and iNOS; the long lasting sources for superoxides (O2-·) and nitric oxides (NO·), respectively (Romero-Graillet et al., 1996; Valencia and Kochevar, 2008). These free radicals cause a peroxinitrite (ONOO−) spike (~400 times increase in the flux per hour) that in turn degrades melanin to its degradation products. The melanin degradation products and peroxinitrite were found to pass freely across nuclear membrane of the melanosomes. Therefore, inside the melanosome nucleus the high energy peroxinitrite excites an electron on melanin fragments to form a high energy triplet carbonyl state which has the high energy of a UV photon. This energy is transferred to nascent DNA generating C → T CPDs in the dark, which are prone to be deaminated inducing a C to T transition by tranlesion polymerases (Choi et al., 2006). The sustained generation of dark CPDs is primarily determined by the persistent generation of NOX and iNOS levels by UVA radiation. Hence the study by Brash and his colleagues suggests that melanin might act as a molecular vector by promoting UVR mediated dark CPDs through chemiexcitation and consequently promote UVA mediated melanomagenesis in pigmented mice as previously reported (Noonan et al., 2012). 
 
In conclusion, UVB-melanomagenesis is independent of melanin and induces direct mutagenic DNA photoproducts (Figure ​(Figure1).1). In contrast UVA-melanomagenesis is pigment-dependent through oxidative DNA damage where melanin acts as a molecular vector in promoting the disease. The generation of dark CPDs by UVA, a major component of sunlight and tanning beds, suggests that the effects of UVR have been underestimated to date and pose a greater risk overall but are quite avertable. Intervention with superoxide inhibitors like α-tocopherol (Vitamin E) and others like- VAS2870 (NOX inhibitor), amino guanidine (iNOS inhibitor), and Ethyl Sorbate a specific quencher of triplet state were found to completely block dark CPD generation. These inhibitors might be used in sunscreens as preventative measures to protect from direct sunlight as well as from post sun exposure (Premi et al., 2015). Overall these studies show a possible role of melanin in promoting UV-induced melanomagenesis. However, previous studies have shown that melanin plays a protective role in UVR mediated skin cancer in dark skinned individuals with eumelanin by shielding against UV radiation, while pheomelanin is harmful by inducing ROS and DNA strand breaks (Chedekel et al., 1978; Takeuchi et al., 2004; Brenner and Hearing, 2008). This raises the question: Is melanin protective or carcinogenic? Indeed, this still requires thorough investigation. 
 
 
 
Figure 1 
 
Role of melanin in immediate and after-effects of UV-DNA damage and melanomagenesis. (A) UVA induces indirect photo-oxidative DNA damage by generating CPDs and 8-oxodG, immediately after irradiation. As a delayed response, UVA induces a significant amount ...}, journal={Frontiers in physiology}, year={2015}, month={Oct} }
 @article{development and validation of a new transgenic hairless albino mouse as a mutational model for potential assessment of photocarcinogenicity._2015, url={https://doi.org/10.1016/j.mrgentox.2015.08.001}, DOI={10.1016/j.mrgentox.2015.08.001}, abstractNote={Short-term phototoxicity testing is useful in selecting test agents for the longer and more expensive photocarcinogenesis safety tests; however, no validated short-term tests have been proven reliable in predicting the outcome of a photocarcinogenesis safety test. A transgenic, hairless, albino (THA) mouse model was developed that carries the gpt and red/gam [Spi(-)] genes from the gpt delta mouse background and the phenotypes from the SKH-1 mouse background to use as a short-term test in lieu of photocarcinogenesis safety tests. Validation of the THA mouse model was confirmed by exposing groups of male mice to sub-erythemal doses of ultraviolet B (UVB) irradiation for three consecutive days emitted from calibrated overhead, Kodacel-filtered fluorescent lamps and measuring the mutant frequencies (MFs) in the gpt and red/gam (Spi(-)) genes and types of mutations in the gpt gene. The doses or irradiation were monitored with broad-spectrum dosimeters that were calibrated to a NIST-traceable standard and cumulative CIE-weighted doses were 20.55 and 41.0mJ/cm(2) (effective). Mice were sacrificed 14 days after the final UVB exposure and MFs in both the gpt and red/gam genes were evaluated in the epidermis. The exposure of mice to UVB induced significant ten- to twelve-fold increases in the gpt MF and three- to five-fold increases in the Spi(-) MF over their respective background MF, 26±3×10(-6) and 9±1×10(-6). The gpt mutation spectra were significantly different between that of the UVB-irradiated and that of non-irradiated mice although the mutation spectra of both groups were dominated by C→T transitions (84% and 66%). In mice exposed to UVB, the C→T transitions occurred almost exclusively at dipyrimidine sites (92%), whereas in non-irradiated control mice, the C→T transitions occurred at CpG sites (86%). These results suggest that the newly developed THA mice are a useful and reliable model for testing UVB-induced mutagenicity in skin tissue. The application of this model for short-term prediction of solar-induced skin carcinogenicity is presently under investigation.}, journal={Mutation research. Genetic toxicology and environmental mutagenesis}, year={2015}, month={Aug} }
 @article{oncogenic braf(v600e) induces clastogenesis and uvb hypersensitivity._2015, url={https://europepmc.org/articles/PMC4491700}, DOI={10.3390/cancers7020825}, abstractNote={The oncogenic BRAF(V600E) mutation is common in melanomas as well as moles. The roles that this mutation plays in the early events in the development of melanoma are poorly understood. This study demonstrates that expression of BRAF(V600E) is not only clastogenic, but synergizes for clastogenesis caused by exposure to ultraviolet radiation in the 300 to 320 nM (UVB) range. Expression of BRAF(V600E) was associated with induction of Chk1 pS280 and a reduction in chromatin remodeling factors BRG1 and BAF180. These alterations in the Chk1 signaling pathway and SWI/SNF chromatin remodeling pathway may contribute to the clastogenesis and UVB sensitivity. These results emphasize the importance of preventing sunburns in children with developing moles.}, journal={Cancers}, year={2015}, month={Jun} }
 @article{the circadian clock controls sunburn apoptosis and erythema in mouse skin_2015, url={https://publons.com/wos-op/publon/48039280/}, DOI={10.1038/JID.2014.508}, abstractNote={Epidemiological studies of humans and experimental studies with mouse models suggest that sunburn resulting from exposure to excessive UV light and damage to DNA confers an increased risk for melanoma and non-melanoma skin cancer. Previous reports have shown that both nucleotide excision repair, which is the sole pathway in humans for removing UV photoproducts, and DNA replication are regulated by the circadian clock in mouse skin. Furthermore, the timing of UV exposure during the circadian cycle has been shown to affect skin carcinogenesis in mice. Because sunburn and skin cancer are causally related, we investigated UV-induced sunburn apoptosis and erythema in mouse skin as a function of circadian time. Interestingly, we observed that sunburn apoptosis, inflammatory cytokine induction, and erythema were maximal following an acute early-morning exposure to UV and minimal following an afternoon exposure. Early-morning exposure to UV also produced maximal activation of ataxia telangiectasia mutated and Rad3-related (Atr)-mediated DNA damage checkpoint signaling, including activation of the tumor suppressor p53, which is known to control the process of sunburn apoptosis. These data provide early evidence that the circadian clock has an important role in the erythemal response in UV-irradiated skin. The early morning is when DNA repair is at a minimum, and thus the acute responses likely are associated with unrepaired DNA damage. The prior report that mice are more susceptible to skin cancer induction following chronic irradiation in the AM, when p53 levels are maximally induced, is discussed in terms of the mutational inactivation of p53 during chronic irradiation.}, journal={Journal of Investigative Dermatology}, year={2015} }
 @article{dna repair synthesis and ligation affect the processing of excised oligonucleotides generated by human nucleotide excision repair._2014, url={https://europepmc.org/articles/PMC4176238}, DOI={10.1074/jbc.m114.597088}, abstractNote={Background: The mechanism of excised oligonucleotide processing during nucleotide excision repair is unknown. Results: UV photoproduct-containing oligonucleotides associate with chromatin following the dual incisions. Inhibition of gap-filling activities results in an accumulation of RPA-bound small, excised, damaged DNA (sedDNA) fragments. Conclusion: Gap filling-mediated dissociation of sedDNAs from RPA influences nucleotide excision repair rate. Significance: sedDNA processing is important in the DNA damage response. Ultraviolet (UV) photoproducts are removed from genomic DNA by dual incisions in humans in the form of 24- to 32-nucleotide-long oligomers (canonical 30-mers) by the nucleotide excision repair system. How the small, excised, damage-containing DNA oligonucleotides (sedDNAs) are processed in cells following the dual incision event is not known. Here, we demonstrate that sedDNAs are localized to the nucleus in two biochemically distinct forms, which include chromatin-associated, transcription factor II H-bound complexes and more readily solubilized, RPA-bound complexes. Because the nuclear mobility and repair functions of transcription factor II H and RPA are influenced by post-incision gap-filling events, we examined how DNA repair synthesis and DNA ligation affect sedDNA processing. We found that although these gap filling activities are not essential for the dual incision/sedDNA generation event per se, the inhibition of DNA repair synthesis and ligation is associated with a decrease in UV photoproduct removal rate and an accumulation of RPA-sedDNA complexes in the cell. These findings indicate that sedDNA processing and association with repair proteins following the dual incisions may be tightly coordinated with gap filling during nucleotide excision repair in vivo.}, journal={The Journal of biological chemistry}, year={2014}, month={Aug} }
 @article{dual modes of clock:bmal1 inhibition mediated by cryptochrome and period proteins in the mammalian circadian clock._2014, url={https://europepmc.org/articles/PMC4173159}, DOI={10.1101/gad.249417.114}, abstractNote={The mammalian circadian clock is based on a transcription–translation feedback loop (TTFL) in which CLOCK and BMAL1 proteins act as transcriptional activators of Cryptochrome and Period genes, which encode proteins that repress CLOCK–BMAL1 with a periodicity of ∼24 h. In this model, the mechanistic roles of CRY and PER are unclear. Here, we used a controlled targeting system to introduce CRY1 or PER2 into the nuclei of mouse cells with defined circadian genotypes to characterize the functions of CRY and PER. Our data show that CRY is the primary repressor in the TTFL: It binds to CLOCK–BMAL1 at the promoter and inhibits CLOCK–BMAL1-dependent transcription without dissociating the complex (“blocking”-type repression). PER alone has no effect on CLOCK–BMAL1-activated transcription. However, in the presence of CRY, nuclear entry of PER inhibits transcription by displacing CLOCK–BMAL1 from the promoter (“displacement”-type repression). In light of these findings, we propose a new model for the mammalian circadian clock in which the negative arm of the TTFL proceeds by two different mechanisms during the circadian cycle.}, journal={Genes & development}, year={2014}, month={Sep} }
 @article{highly specific and sensitive method for measuring nucleotide excision repair kinetics of ultraviolet photoproducts in human cells_2014, url={https://publons.com/wos-op/publon/9035191/}, DOI={10.1093/NAR/GKT1179}, abstractNote={Abstract}, journal={Nucleic Acids Research}, year={2014} }
 @article{dna damage-specific control of cell death by cryptochrome in p53-mutant ras-transformed cells_2013, url={https://publons.com/wos-op/publon/9037698/}, DOI={10.1158/0008-5472.CAN-12-1994}, abstractNote={Abstract}, journal={Cancer Research}, year={2013} }
 @article{nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying dna damage in vivo._2013, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23749995/?tool=EBI}, DOI={10.1074/jbc.m113.482257}, abstractNote={Background: Human excision repair removes UV photoproducts in 30-mers in vitro, but this has not been previously observed in vivo. Results: UV photoproducts are removed in vivo as 30-mers in complex with TFIIH both in general repair and in transcription-coupled repair. Conclusion: Primary products of excision repair have been isolated in vivo for the first time. Significance: The study provides novel insights into post-excision steps of human DNA repair. Nucleotide excision repair is the sole mechanism for removing the major UV photoproducts from genomic DNA in human cells. In vitro with human cell-free extract or purified excision repair factors, the damage is removed from naked DNA or nucleosomes in the form of 24- to 32-nucleotide-long oligomers (nominal 30-mer) by dual incisions. Whether the DNA damage is removed from chromatin in vivo in a similar manner and what the fate of the excised oligomer was has not been known previously. Here, we demonstrate that dual incisions occur in vivo identical to the in vitro reaction. Further, we show that transcription-coupled repair, which operates in the absence of the XPC protein, also generates the nominal 30-mer in UV-irradiated XP-C mutant cells. Finally, we report that the excised 30-mer is released from the chromatin in complex with the repair factors TFIIH and XPG. Taken together, our results show the congruence of in vivo and in vitro data on nucleotide excision repair in humans.}, journal={The Journal of biological chemistry}, year={2013}, month={Jun} }
 @article{effect of circadian clock mutations on dna damage response in mammalian cells._2012, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22918252/?tool=EBI}, DOI={10.4161/cc.21771}, abstractNote={The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents.}, journal={Cell cycle (Georgetown, Tex.)}, year={2012}, month={Aug} }
 @article{gaddameedhi_selby_kaufmann_smart_sancar_2011, title={Control of skin cancer by the circadian rhythm}, volume={108}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1115249108}, DOI={10.1073/pnas.1115249108}, abstractNote={Skin cancer is the most common form of cancer in the United States. The main cause of this cancer is DNA damage induced by the UV component of sunlight. In humans and mice, UV damage is removed by the nucleotide excision repair system. Here, we report that a rate-limiting subunit of excision repair, the xeroderma pigmentosum group A (XPA) protein, and the excision repair rate exhibit daily rhythmicity in mouse skin, with a minimum in the morning and a maximum in the afternoon/evening. In parallel with the rhythmicity of repair rate, we find that mice exposed to UV radiation (UVR) at 4:00 AM display a decreased latency and about a fivefold increased multiplicity of skin cancer (invasive squamous cell carcinoma) than mice exposed to UVR at 4:00 PM. We conclude that time of day of exposure to UVR is a contributing factor to its carcinogenicity in mice, and possibly in humans.}, number={46}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Gaddameedhi, S. and Selby, C. P. and Kaufmann, W. K. and Smart, R. C. and Sancar, A.}, year={2011}, month={Oct}, pages={18790–18795} }
 @article{melanoma and dna damage from a distance (farstander effect)._2011, url={https://doi.org/10.1111/j.1755-148X.2010.00805.x}, DOI={10.1111/j.1755-148x.2010.00805.x}, abstractNote={It has been known for a long time that cancer, even in the absence of metastasis, has adverse systemic effects on the organism. The mechanism of these global effects is complex. A clue to the possible mechanism comes from what is known about the bystander effect (BE). Although BE has been used to describe the reaction in tissue adjacent to the irradiated area more generally the term is applied to the effect of cancer cells on the adjacent normal tissue. It is generally believed that cytokines such as TGF-b and reactive oxygen species (ROS) released from cancer cells mediate the BE. The paper by Redon et al. (2010) shows that the same or similar mechanisms that are responsible for BE may cause systemic effects as well (farstander effect, FE). These findings provide significant insight into the systemic effects of cancer as well as the potential link between chronic inflammation and cancer. The basic experimental design of Redon et al. (2010) was to subcutaneously implant B16 melanoma and M5076 reticulum sarcoma into syngeneic C57BL ⁄ 6 mice and similarly COLON26 carcinoma into syngeneic BALB ⁄ C mice. After the tumors reached about 200 mg, the animals were sacrificed to look for systemic genotoxic stress, as determined by DNA damage checkpoint response (Sancar et al., 2004) and oxidative base damage. For DNA damage checkpoint response, the authors measured H2AX phosphorylation, which is a classical sign of the checkpoint response to DNA double-strand breaks (DSBs). As a readout for oxidative damage they measured thymine glycols, 8-oxoguanine, and apurinic ⁄ apyrimidinic (AP sites) in DNA, all known to be induced by ROS. The authors found that all three cancers induced systemic effects on distant organs, but only in those organs in which there is active cell proliferation, such as the gastrointestinal tract (GIT) and the skin. These results suggest that S-phase cells of the skin and GIT are more sensitive to DSB formation through FE, as seen previously for BE in an IR-induced cell culture system (Burdak-Rothkamm et al., 2007; BurdakRothkamm et al., 2008). Importantly, Redon et al. also show that at the hair bulb (where stem cells are located) of the hair follicles in the skin, as well as at base of the duodenum (where proliferating cells are located) of the tumor implanted mice have up to threefold more cH2AX foci than at the other parts of the same tissue. Even though the authors did not look for stem cell markers at the base of the hair bulb or at the duodenum, it is likely that the elevated cH2AX foci are from the stem cells which may be more sensitive to tumor-induced near and far signals. Figure 1 shows the schematic representation of the tumor-induced spontaneous systemic FE response in vivo. Previous studies have indicated that the macrophage-mediated inflammatory response of the radiation-induced damaged cells may be responsible for}, journal={Pigment cell & melanoma research}, year={2011}, month={Feb} }
 @article{similar nucleotide excision repair capacity in melanocytes and melanoma cells._2010, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20501836/?tool=EBI}, DOI={10.1158/0008-5472.can-10-0095}, abstractNote={Abstract}, journal={Cancer research}, year={2010}, month={May} }
 @article{association between the unfolded protein response, induced by 2-deoxyglucose, and hypersensitivity to cisplatin: a mechanistic study employing molecular genomics._2009, url={https://doi.org/10.4103/0973-1482.55146}, DOI={10.4103/0973-1482.55146}, abstractNote={BACKGROUND
The specific signaling that occurs between the endoplasmic reticulum (ER) and the nucleus in response to ER stress is known as the unfolded protein response (UPR). Specific induction of GRP78 (glucose-regulated protein of Mr 78 kDa) is an integral component of ER stress and the UPR. We first discovered that the up-regulation of GRP78 is associated with augmented sensitivity/apoptosis of cancer cells to clinically used alkylating/platinating agents.


OBJECTIVES
To decipher molecular mechanisms that associate induction of the UPR/GRP78 with augmented sensitivity/apoptosis to cisplatin.


MATERIALS AND METHODS
A549 cells were exposed to 2-deoxyglucose (2dG) to induce the UPR/GRP78, followed by cisplatin treatment. We used human cDNA microarray containing 42,000 ESTs as well as pathway-specific macroarrays for apoptosis, cell cycle, and MAP kinase signaling pathways containing 100-280 genes and subsequently examined the pertinent transcript levels. The results obtained from these studies were confirmed by examining relevant protein levels and the enzymatic activity.


RESULTS
We demonstrate that the induction of UPR/GRP78 alone causes a decrease in the transcript levels of DNA repair genes and DNA damage check point genes, and an increase in the transcript levels of apoptotic genes. Furthermore, we show that cisplatin treatment after the induction of UPR/GRP78 is facilitating the mitochondria-mediated apoptotic cascades through the initial activation of caspase-2 and down-regulation of genes involved in DNA repair.


CONCLUSIONS
Our study will shed new insight as to the increased understanding of the mechanisms of the UPR/GRP78 modulation of molecular and cellular responses to cisplatin that will allow strategies for transferring bench side results to the bed.}, journal={Journal of cancer research and therapeutics}, year={2009}, month={Sep} }
 @article{loss of cryptochrome reduces cancer risk in p53 mutant mice._2009, url={https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19188586/?tool=EBI}, DOI={10.1073/pnas.0813028106}, abstractNote={
            It is commonly thought that disruption of the circadian clock increases the cancer incidence in humans and mice. However, it was found that disruption of the clock by the
            Cryptochrome
            (
            Cry
            ) mutation in mice did not increase cancer rate in the mutant mice even after exposing the animals to ionizing radiation. Therefore, in this study we tested the effect of the
            Cry
            mutation on carcinogenesis in a mouse strain prone to cancer because of a
            p53
            mutation, with the expectation that clock disruption in this sensitized background would further increase cancer risk. Paradoxically, we find that the
            Cry
            mutation protects
            p53
            mutant mice from the early onset of cancer and extends their median lifespan ≈50%, in part by sensitizing
            p53
            mutant cells to apoptosis in response to genotoxic stress. These results suggest alternative therapeutic approaches in management of cancers associated with a
            p53
            mutation.
          }, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2009}, month={Feb} }
 @article{deciphering the association between up-regulation of glucose regulated protein of mr-78 kda (grp78) and hypersensitivity to cisplatin employing comparative genomics_2008, url={https://publons.com/wos-op/publon/54906423/}, journal={The FASEB Journal}, year={2008} }
 @article{up-regulation of glucose regulated protein of m-r-78kda (grp78) followed by cisplatin treatment leads to mitochondrial mediated apoptosis through caspase-2 activation_2006, url={https://publons.com/wos-op/publon/54906422/}, journal={Cancer Research}, year={2006} }
 @article{in-gel precipitation of enzymatically released phosphate._2004, url={https://doi.org/10.1016/j.ab.2004.07.010}, DOI={10.1016/j.ab.2004.07.010}, abstractNote={The phosphate precipitation reaction using ammonium molybdate and triethylamine under low pH has been applied to gel-based assays for detecting phosphate-releasing enzymes. The sensitivity of the assay is 10 pmol Pi/mm2 of 1.5-mm-thick gel. The assay is applicable to enzymes with a wide range of optimal pH, from acid (pH 4.5) to alkaline phosphatase (pH 9.7), and to enzymes that use acid-labile substrates such as apyrase and glutamine synthetase. Using a negative staining approach, maltose phosphorylase, a phosphate-consuming enzyme, can also be detected. The assay was used to detect glutamine synthetase isoforms, separated by nondenaturing polyacrylamide gel electrophoresis from crude maize extracts. For downstream applications such as staining gels for proteins, the gels with precipitate should be incubated in 10 mM dithiothreitol or beta-mercaptoethanol until the precipitate is dissolved and then thoroughly washed in water. In comparison to calcium phosphate precipitation or the phosphomolybdate-malachite green method, this method is more sensitive. It is a very simple, rapid, versatile, reproducible, and inexpensive method that could be a useful tool in enzymological studies.}, journal={Analytical biochemistry}, year={2004}, month={Nov} }