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BACKGROUND: This study had aimed to describe long-term decision regret, bowel dysfunction, and the overall quality of life in patients with diverticulitis, and to determine if elective colectomy was associated with these patient-reported outcome measures. METHODS: This mixed-methods, survey-based study was administered to a national cohort of patients in the United States with diverticulitis. We measured decision regret (Brehaut Decision Regret), bowel dysfunction (Low Anterior Resection Syndrome score), and the overall quality of life (EuroQol 5 Dimension) in this population. We asked open-ended questions to elucidate factors that influenced patients’ choices between elective colectomy and observation. RESULTS: Among the 614 respondents, 294 (48%) chose between colectomy and observational management, 94 (15%) had surgery, and 157 (26%) had major Low Anterior Resection Syndrome. Of the 294 that chose between colectomy and observational management, 51 (17%) experienced decision regret. Colectomy was associated with an average decrease in the Brehaut Decision Regret score by 6 points but was not associated with a categorical measure of decision regret (Brehaut Score ≥50). Bowel dysfunction and overall quality of life were not significantly associated with colectomy. Disease-related factors, psychosocial factors, and interactions with physicians were commonly cited as reasons for pursuing colectomy or observational management. CONCLUSION: Patients with self-reported diverticulitis describe high levels of decision regret and bowel dysfunction regardless of chosen management strategy. Physicians should be aware that psychosocial factors can strongly influence a patient’s choice between colectomy and observational management. We advocated for future prospective studies using patient reported outcome metrics to improve outcomes in diverticulitis.

OBJECTIVE: The purpose of this study was to examine the literature regarding the natural history and rehabilitative outcomes of sensorineural hearing loss from congenital cytomegalovirus infections. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: A systematic search was performed in PubMed, PsychINFO, CINAHL, and Web of Science to identify peer-reviewed research. Eligible studies were those containing original peer-reviewed research in English addressing either the natural history or rehabilitative outcomes of SNHL in cCMV. STUDY APPRAISAL AND SYNTHESIS METHODS: Two investigators independently reviewed all articles and extracted data. Bias was assessed using the Cochrane Collaboration’s tool and the Newcastle-Ottawa Assessment Scale. RESULTS: Thirty-six articles were reviewed. Universal screening identifies 0.2 – 1% of newborns with cCMV infection. SNHL ranged from 8–32% of infants and was more prevalent in symptomatic vs. asymptomatic cases. 9 – 68% of hearing loss occurs in a late or delayed fashion. In 7–71% of cases hearing loss is progressive. Cochlear implantation is a viable option for patients with cCMV associated hearing loss and leads to improvements in hearing and language. There is limited literature comparing rehabilitation outcomes in cCMV and non-cCMV CI recipients. CONCLUSION: Late onset and progressive hearing loss is seen in children who develop hearing loss from cCMV. Frequent audiologic follow-up is necessary considering the natural history of cCMV hearing loss. Universal screening should be pursued due to the number of asymptomatic children, at birth, who develop late onset/delayed hearing loss. Cochlear implantation is an effective means of improving speech and language in this population.

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5΄ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5′ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.

The melanocortin 1 receptor (MC1R), a GS-coupled receptor that signals through cAMP and PKA, regulates pigmentation, adaptive tanning, and melanoma resistance. MC1R-cAMP signaling promotes PKA-mediated phosphorylation of ataxia telangiectasia and rad3-related (ATR) at Ser435 (ATR-pS435), a modification that enhances nucleotide excision repair (NER) by facilitating recruitment of the XPA protein to sites of UV-induced DNA damage. High-throughput methods were developed to quantify ATR-pS435, measure XPA-photodamage interactions and assess NER function. We report that melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone (ACTH) induce ATR-pS435, enhance XPA’s association with UV-damaged DNA and optimize melanocytic NER. In contrast, MC1R antagonists agouti signaling protein (ASIP) or human β-defensin 3 (HBD3) interfere with ATR-pS435 generation, impair the XPA-DNA interaction and reduce DNA repair. Although ASIP and HBD3 each blocked α-MSH-mediated induction of the signaling pathway, only ASIP depleted basal ATR-pS435. Our findings confirm that ASIP diminishes agonist-independent MC1R basal signaling whereas HBD3 is a neutral MC1R antagonist that blocks activation by melanocortins. Furthermore, our data suggest that ATR-pS435 may be a useful biomarker for the DNA repair-deficient MC1R phenotype.

Key points The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1−/−) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity. Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1−/−), a model of advanced ageing. iMSBmal1−/− mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing. Abstract Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription–translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1−/− mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone.

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Loss-of-function in melanocortin 1 receptor (MC1R), a G

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair, the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts nucleotide excision repair.

UV radiation is a pervasive environmental agent that affects the skin in complex ways. It benefits human health by its contribution to the biosynthesis of vitamin D in the skin, however it also is a major carcinogen responsible for millions of skin cancers diagnosed each year. One of the most important physiologic responses recruited with UV exposure is the melanocortin signaling axis. This pathway, initiated by melanocortins such as melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone (ACTH), is dependent on the signaling function of the melanocortin 1 receptor (MC1R), a Gs protein-coupled cell surface receptor found on melanocytes in the skin. MC1R mediates its downstream UV-protective responses through activation of adenylyl cyclase and production of the second messenger cAMP. In melanocytes, cAMP stimulation leads to improved survival and UV-defensive sequelae. Here, we review how MC1R signaling protects melanocytes from UV-induced malignant degeneration, focusing on recent insights into molecular links between MC1R signaling and the nucleotide excision repair (NER) genome maintenance pathway. Finally, we highlight how insights into the MC1R UV protective response may facilitate the development of rational melanoma-protective strategies.

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic Gs-coupled transmembrane receptor activated by binding to its high-affinity ligand, α-melanocyte stimulating hormone (MSH). Besides influencing pigment phenotype and mediating adaptive tanning, MC1R signaling is intricately linked with genome maintenance and DNA repair. Individuals harboring loss-of-function MC1R polymorphisms are UV sensitive and melanoma-prone. We have determined that MC1R-mediated cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435 which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing UV mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA and elevates UV-induced mutagenesis. PKA-mediated ATR phosphorylation on Ser435 appears to induce a DNA repair-specific function of ATR independent of Chk1 phosphorylation and cell cycle arrest. Importantly, MC1R signaling defects and sub-optimal DNA repair are overcome by forskolin-mediated cAMP induction in melanocytes and in whole skin. Our findings mechanistically link cAMP-PKA signaling to NER and illustrate the potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals. Citation Format: Stuart Gordon Jarrett, Erin M. Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue Zou, John August D'Orazio. MC1R signaling reduces UV mutagenesis by ATR-mediated recruitment of XPA to photolesions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A34.

In order to determine the effect of UV radiation on β-defensin 3 (BD3) expression in human skin, freshly-isolated UV-naïve skin was obtained from newborn male infants undergoing planned circumcision. Skin explants sustained ex vivo dermis side down on RPMI media were exposed to 0.5 kJ/m2UVB, and biopsies were taken from the explant through 72 hours after radiation. mRNA expression was measured by qRTPCR and normalized to TATA-binding protein. BD3 expression at each time point was compared with an untreated control taken at time 0 within each skin sample. Extensive variability in both the timing and magnitude of BD3 induction across individuals was noted and was not predicted by skin pigment phenotype, suggesting that BD3 induction was not influenced by epidermal melanization. However, a mock-irradiated time course demonstrated UV-independent BD3 mRNA increases across multiple donors which was not further augmented by treatment with UV radiation, suggesting that factors other than UV damage promoted increased BD3 expression in the skin explants. We conclude that BD3 expression is induced in a UV-independent manner in human skin explants processed and maintained in standard culture conditions, and that neonatal skin explants are an inappropriate model with which to study the effects of UV on BD3 induction in whole human skin.