Caffeine stabilises fission yeast Wee1 in a Rad24-dependent manner but attenuates its expression in response to DNA damage identifying a putative role for TORC1 in mediating its effects on cell cycle progression

The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine’s inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine therefore modulates cell cycle progression contextually through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition

Caffeine Stabilises Fission Yeast Wee1 in a Rad24-Dependent Manner but Attenuates Its Expression in Response to DNA Damage

The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine’s inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine may modulate cell cycle progression through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition, as TORC1 inhibition increased DNA damage sensitivity

What is known about the health and living conditions of the indigenous people of northern Scandinavia, the Sami?

The Sami are the indigenous ethnic population of northern Scandinavia. Their health condition is poorly known, although the knowledge has improved over the last decade.The aim was to review the current information on mortality, diseases, and risk factor exposure in the Swedish Sami population.Health-related research on Sami cohorts published in scientific journals and anthologies was used to compare the health condition among the Sami and the majority non-Sami population. When relevant, data from the Sami populations in Swedish were compared with corresponding data from Norwegian and Finnish Sami populations.Life expectancy and mortality patterns of the Sami are similar to those of the majority population. Small differences in incidences of cancer and cardiovascular diseases have been reported. The traditional Sami lifestyle seems to contain elements that reduce the risk to develop cancer and cardiovascular diseases, e.g. physical activity, diet rich in antioxidants and unsaturated fatty acids, and a strong cultural identity. Reindeer herding is an important cultural activity among the Sami and is associated with high risks for accidents. Pain in the lower back, neck, shoulders, elbows, and hands are frequent among both men and women in reindeer-herding families. For men, these symptoms are related to high exposure to terrain vehicles, particularly snowmobile, whereas for women psychosocial risk factors seem to more important, e.g. poor social support, high effort, low reward, and high economical responsibilities.Although the health condition of the Sami population appears to be rather similar to that of the general Swedish population, a number of specific health problems have been identified, especially among the reindeer-herding Sami. Most of these problems have their origin in marginalization and poor knowledge of the reindeer husbandry and the Sami culture in the majority population. It is suggested that the most sustainable measure to improve the health among the reindeer-herding Sami would be to improve the conditions of the reindeer husbandry and the Sami culture

Aspirin and other non-steroidal anti-inflammatory drugs and depression, anxiety, and stress-related disorders following a cancer diagnosis: a nationwide register-based cohort study

Publisher's version (útgefin grein)Background: Cancer patients have a highly increased risk of psychiatric disorders following diagnosis, compared with cancer-free individuals. Inflammation is involved in the development of both cancer and psychiatric disorders. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in the subsequent risk of psychiatric disorders after cancer diagnosis is however unknown. Methods: We performed a cohort study of all patients diagnosed with a first primary malignancy between July 2006 and December 2013 in Sweden. Cox proportional hazards models were used to assess the association of NSAID use during the year before cancer diagnosis with the risk of depression, anxiety, and stress-related disorders during the first year after cancer diagnosis. Results: Among 316,904 patients identified, 5613 patients received a diagnosis of depression, anxiety, or stress-related disorders during the year after cancer diagnosis. Compared with no use of NSAIDs, the use of aspirin alone was associated with a lower rate of depression, anxiety, and stress-related disorders (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81 to 0.97), whereas the use of non-aspirin NSAIDs alone was associated with a higher rate (HR, 1.24; 95% CI, 1.15 to 1.32), after adjustment for sociodemographic factors, comorbidity, indications for NSAID use, and cancer characteristics. The association of aspirin with reduced rate of depression, anxiety, and stress-related disorders was strongest for current use (HR, 0.84; 95% CI, 0.75 to 0.93), low-dose use (HR, 0.88; 95% CI, 0.80 to 0.98), long-term use (HR, 0.84; 95% CI, 0.76 to 0.94), and among patients with cardiovascular disease (HR, 0.81; 95% CI, 0.68 to 0.95) or breast cancer (HR, 0.74; 95% CI, 0.56 to 0.98). Conclusion: Pre-diagnostic use of aspirin was associated with a decreased risk of depression, anxiety, and stress-related disorders during the first year following cancer diagnosis.This study was supported by grants awarded to FF by Swedish Cancer Society (No. CAN 2017/322) and the Swedish Research Council for Health, Working Life and Welfare (No. 2017-00531), to KH by China Scholarship Council (No. 201806240005), to ES by National Health and Medical Research Council (GNT1147498) and National Breast Cancer Foundation (IIRS-20 to 025), and to AW by the National Breast Cancer Foundation (PF-15 to 014). The researchers were independent of the funding agencies. The funding bodies have no role in the design of the study or collection, analysis, and interpretation of data or in writing the manuscript. Open access funding provided by Karolinska Institute.Peer Reviewe

Background risk of breast cancer and the association between physical activity and mammographic density

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Linkage disequilibrium mapping of CHEK2: Common variation and breast cancer risk

10.1371/journal.pmed.0030168PLoS Medicine360895-090

ESR1 and EGF genetic variation in relation to breast cancer risk and survival

The main purposes of this thesis were to analyse common genetic variation in candidate genes and candidate pathways in relation to breast cancer risk, prognosticators and survival, to develop statistical methods for genetic association analysis for evaluating the joint importance of genes, and to investigate the potential impact of adding genetic information to clinical risk factors for projecting individualised risk of developing breast cancer over specific time periods. In Paper I we studied genetic variation in the estrogen receptor α and epidermal growth factor genes in relation to breast cancer risk and survival. We located a region in the estrogen receptor α gene which showed a moderate signal for association with breast cancer risk but were unable to link common variation in the epidermal growth factor gene with breast cancer aetiology or prognosis. In Paper II we investigated whether suspected breast cancer risk SNPs within genes involved in androgen-to-estrogen conversion are associated with breast cancer prognosticators grade, lymph node status and tumour size. The strongest association was observed for a marker within the CYP19A1 gene with histological grade. We also found evidence that a second marker from the same gene is associated with histological grade and tumour size. In Paper III we developed a novel test of association which incorporates multivariate measures of categorical and continuous heterogeneity. In this work we described both a single-SNP and a global multi-SNP test and used simulated data to demonstrate the power of the tests when genetic effects differ across disease subtypes. In Paper IV we assessed the extent to which recently associated genetic risk variants improve breast cancer risk-assessment models. We investigated empirically the performance of eighteen breast cancer risk SNPs together with mammographic density and clinical risk factors in predicting absolute risk of breast cancer. We also examined the usefulness of various prediction models considered at a population level for a variety of individualised breast cancer screening approaches. The goal of a genetic association study is to establish statistical associations between genetic variants and disease states. Each variant linked to a disease can lead the way to a better understanding of the underlying biological mechanisms that govern the development of a disease. Increased knowledge of molecular variation provides the opportunity to stratify populations according to genetic makeup, which in turn has the potential to lead to improved disease prevention programs and improved patient care

A sensory role for the cruciate ligaments : regulation of joint stability via reflexes onto the γ-muscle-spindle system

Reflex effects evoked by graded electrical stimulation of the posterior articular nerves (PAN) of the ipsi- and contralateral knee joints were investigated using both micro-electrode recordings from 7 - motoneurones and recordings from single muscle muscle spindle afferents. Spindle afferent responses were also recorded using natural stimulation of different types of receptors, to elucidate if the articular reflexes onto the y -motoneurones were potent enough to significantly alter the muscle spindle afferent activity. Stretches of the ipsilateral posterior (PCL) and anterior (ACL) cruciate ligaments, pressure on the ipsi- and contralateral knee and ankle joint capsules, and passive flexion/extension movements of the joints in the contralateral hind limb were performed. The occurrance of different sensory endings in the ACL and PCL was examined using gold chloride staining for neuronal elements. All experiments were performed on chloralose anaesthetized cats. More than 90% of the static and dynamic y -motoneurones were responsive to electrical stimulation of the PAN. Most 7-cells responded to low intensity electrical stimulation. Excitatoiy reflex effects predominated on both static and dynamic posterior biceps-semitendinosus (PBSt) 7 -cells, while excitatory and inhibitory effects occurred with an about equal frequency on triceps-plantaris (GS) 7-cells. The fastest segmental route for excitatory PAN effects on hind limb 7-motoneurones seems to be di- or trisynaptic, while the path for inhibitory effects seems to be at least one synaps longer. Physiological stimulations of ipsi- and contralateral joint capsules and of ipsilateral cruciate ligaments were all found to evoke frequent and potent changes in spindle afferent responses from the GS and PBSt muscles. It was shown that these effects were due to reflexes onto dynamic and static fusimotor neurones caused by physiological activation of articular sensory endings. Both ipsi- and contralateral joint receptor stimulation evoked excitatory as well as inhibitory fusimotor effects. The highest responsiveness was found during stimula­tion of the cruciate ligaments, i.e. 58% for GS and 47% for PBSt primary spindle afferents to PCL stimula­tion, and 73% for GS and 55% for PBSt primary spindle afferents to ACL stimulation. Significant altera­tions in spindle afferent activity was encountered at very low traction forces applied to the cruciate ligaments (5-10 N). The low thresholds, the tonic character of the stimuli, and the fact that different types of sensory endings were demonstrated in the cruciate ligaments (i.e. Ruffini endings, Pacinian corpuscles, Golgi ten­don organ like endings and free nerve endings), indicate that the fusimotor effects observed were caused by activation of slowly adapting mechanoreceptors, most likely Ruffini endings and/or Golgi tendon organ like endings. The potent reflex effects on the muscle spindle afferents elicited by increased tension in the cruciate ligaments indicate that these ligaments may play a more important sensory role that hitherto believed, and it is suggested that they may be important in the regulation of the stiffness of muscles around the knee joint, and thereby for the joint stability. The possible clinical relevance and the mechanisms by which joint receptor afferents, via adjustment of the muscle stiffness, may control joint stability are discussed.Diss. (sammanfattning) Umeå : Umeå universitet, 1989, härtill 7 uppsatser.digitalisering@um

A sensory role for the cruciate ligaments : regulation of joint stability via reflexes onto the γ-muscle-spindle system

Reflex effects evoked by graded electrical stimulation of the posterior articular nerves (PAN) of the ipsi- and contralateral knee joints were investigated using both micro-electrode recordings from 7 - motoneurones and recordings from single muscle muscle spindle afferents. Spindle afferent responses were also recorded using natural stimulation of different types of receptors, to elucidate if the articular reflexes onto the y -motoneurones were potent enough to significantly alter the muscle spindle afferent activity. Stretches of the ipsilateral posterior (PCL) and anterior (ACL) cruciate ligaments, pressure on the ipsi- and contralateral knee and ankle joint capsules, and passive flexion/extension movements of the joints in the contralateral hind limb were performed. The occurrance of different sensory endings in the ACL and PCL was examined using gold chloride staining for neuronal elements. All experiments were performed on chloralose anaesthetized cats. More than 90% of the static and dynamic y -motoneurones were responsive to electrical stimulation of the PAN. Most 7-cells responded to low intensity electrical stimulation. Excitatoiy reflex effects predominated on both static and dynamic posterior biceps-semitendinosus (PBSt) 7 -cells, while excitatory and inhibitory effects occurred with an about equal frequency on triceps-plantaris (GS) 7-cells. The fastest segmental route for excitatory PAN effects on hind limb 7-motoneurones seems to be di- or trisynaptic, while the path for inhibitory effects seems to be at least one synaps longer. Physiological stimulations of ipsi- and contralateral joint capsules and of ipsilateral cruciate ligaments were all found to evoke frequent and potent changes in spindle afferent responses from the GS and PBSt muscles. It was shown that these effects were due to reflexes onto dynamic and static fusimotor neurones caused by physiological activation of articular sensory endings. Both ipsi- and contralateral joint receptor stimulation evoked excitatory as well as inhibitory fusimotor effects. The highest responsiveness was found during stimula­tion of the cruciate ligaments, i.e. 58% for GS and 47% for PBSt primary spindle afferents to PCL stimula­tion, and 73% for GS and 55% for PBSt primary spindle afferents to ACL stimulation. Significant altera­tions in spindle afferent activity was encountered at very low traction forces applied to the cruciate ligaments (5-10 N). The low thresholds, the tonic character of the stimuli, and the fact that different types of sensory endings were demonstrated in the cruciate ligaments (i.e. Ruffini endings, Pacinian corpuscles, Golgi ten­don organ like endings and free nerve endings), indicate that the fusimotor effects observed were caused by activation of slowly adapting mechanoreceptors, most likely Ruffini endings and/or Golgi tendon organ like endings. The potent reflex effects on the muscle spindle afferents elicited by increased tension in the cruciate ligaments indicate that these ligaments may play a more important sensory role that hitherto believed, and it is suggested that they may be important in the regulation of the stiffness of muscles around the knee joint, and thereby for the joint stability. The possible clinical relevance and the mechanisms by which joint receptor afferents, via adjustment of the muscle stiffness, may control joint stability are discussed.Diss. (sammanfattning) Umeå : Umeå universitet, 1989, härtill 7 uppsatser.digitalisering@um