CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point

Cell cycle progression, including genome duplication, is orchestrated by cyclin-dependent kinases (CDKs). CDK activation depends on phosphorylation of their T-loop by a CDK-activating kinase (CAK). In animals, the only known CAK for CDK2 and CDK1 is cyclin H-CDK7, which is constitutively active. Therefore, the critical activation step is dephosphorylation of inhibitory sites by Cdc25 phosphatases rather than unrestricted T-loop phosphorylation. Homologous CDK4 and CDK6 bound to cyclins D are master integrators of mitogenic/oncogenic signaling cascades by initiating the inactivation of the central oncosuppressor pRb and cell cycle commitment at the restriction point. Unlike the situation in CDK1 and CDK2 cyclin complexes, and in contrast to the weak but constitutive T177 phosphorylation of CDK6, we have identified the T-loop phosphorylation at T172 as the highly regulated step determining CDK4 activity. Whether both CDK4 and CDK6 phosphorylations are catalyzed by CDK7 remains unclear. To answer this question, we took a chemical-genetics approach by using analogue-sensitive CDK7(as/as) mutant HCT116 cells, in which CDK7 can be specifically inhibited by bulky adenine analogs. Intriguingly, CDK7 inhibition prevented activating phosphorylations of CDK4/6, but for CDK4 this was at least partly dependent on its binding to p21(cip1). In response to CDK7 inhibition, p21-binding to CDK4 increased concomitantly with disappearance of the most abundant phosphorylation of p21, which we localized at S130 and found to be catalyzed by both CDK4 and CDK2. The S130A mutation of p21 prevented the activating CDK4 phosphorylation, and inhibition of CDK4/6 and CDK2 impaired phosphorylations of both p21 and p21-bound CDK4. Therefore, specific CDK7 inhibition revealed the following: a crucial but partly indirect CDK7 involvement in phosphorylation/activation of CDK4 and CDK6; existence of CDK4-activating kinase(s) other than CDK7; and novel CDK7-dependent positive feedbacks mediated by p21 phosphorylation by CDK4 and CDK2 to sustain CDK4 activation, pRb inactivation, and restriction point passage

Giant cell arteritis exclusively detected by 18F-fluorodeoxyglucose positron emission tomography: a case report

INTRODUCTION: This case of giant cell arteritis is noteworthy because it evaded standard diagnostic criteria and only emerged as fever of unknown origin. In this regard, we present (18)F-fluorodeoxyglucose positron emission tomography as a valid diagnostic method. CASE PRESENTATION: This case report describes a 58-year-old Caucasian woman who is a cigarette smoker with a 10-week history of fever of unknown origin, night sweats and weight loss of 12kg. Initially, clinical presentation was suspicious of malignant disease. Laboratory findings detected significantly elevated inflammatory blood parameters including C-reactive protein and elevated erythrocyte sedimentation rate (110mm/hour). Extensive diagnostic workup including microbiological and rheumatological assessment, ultrasonography, endoscopy and computed tomography of abdomen and thorax did not indicate any septic or malignant focus. Eventually, (18)F-fluorodeoxyglucose positron emission tomography was able to reveal arteritis of her aortic arch and supraaortic branches. Subsequently, she commenced steroid and methotrexate therapy that led to sustained remission. CONCLUSIONS: This case of giant cell arteritis may promote discussion regarding a more specific classification for this disease entity. Furthermore, it confirms that (18)F-fluorodeoxyglucose positron emission tomography might serve as a valuable tool for diagnosis of giant cell arteritis, because it could facilitate an accurate and non-invasive detection of lesions of large vessels

Teaching ultrasound in a curricular course according to certified EFSUMB standards during undergraduate medical education: a prospective study

Background: As a non-invasive and readily available diagnostic tool, ultrasound is one of the most important imaging techniques in medicine. Ultrasound is usually trained during residency preferable according to German Society of Ultrasound in Medicine (DEGUM) standards. Our curriculum calls for undergraduate training in ultrasound of medical students in their 4th year of undergraduate education. An explorative pilot study evaluated the acceptance of this teaching method, and compared it to other practical activities in medical education at Muenster University. Methods: 240 medical students in their 4th year of undergraduate medical education participated in the training and completed a pre- and post-questionnaire for self-assessment of technical knowledge, self-assurance of the procedure, and motivation in performing ultrasound using a Likert scale. Moreover, students were asked about their interest in pursuing a career in internal medicine. To compare this training to other educational activities a standardized online evaluation tool was used. A direct observation of procedural skills assessment (DOPS) for the first time applied on ultrasound aimed to independently assess the success of our teaching method. Results: There was a significant increase in technical knowledge and self-assurance (p < 0.001) of the students’ self-assessments. The clinical relevance and self-motivation of the teaching were evaluated positively. The students’ DOPS results demonstrated proficiency in the understanding of anatomic structures shown in ultrasonographic images, including terminology, machine settings, and transducer frequencies. Conclusions: Training ultrasound according to certified DEGUM standards was successful and should be offered in undergraduate medical education. The evaluation of the course affirmed the necessity, quality and clinical relevance of the course with a top ranking score of hands-on training courses within the educational activities of the Medical Faculty of Muenster.<br

Eight Weeks of Lifestyle Change: What are the Effects of the Healthy Lifestyle Community Programme (Cohort 1) on Cortisol Awakening Response (CAR) and Perceived Stress?

Background: Stress and cortisol dysregulation are linked to NCDs. Moreover, stress favours unhealthy lifestyle patterns, which increase the risk for NCDs. The role of the Cortisol Awakening Response (CAR) and the effect of lifestyle interventions on the same remain unclear. Methods: The impact of the intensive 8-week phase of the Healthy Lifestyle Community Programme (HLCP, cohort 1) on parameters of the CAR, ie cortisol values 0 (sample [S]1), 30), 45 and 60 minutes post-awakening, average peak, S1-peak delta and area under the increase curve (AUCI), and perceived stress levels (PSL) was evaluated in a non-randomized, controlled trial. Covariates of the CAR (eg sleep measures) and irregularities in sampling were assessed. The intervention focussed on stress management, a healthy diet, regular exercise, and social support. Participants were recruited from the general population. Multiple linear regression analyses were conducted. Results: 97 participants (age: 56±10 years; 71% female), with 68 in the intervention group (IG; age: 55±8, 77% female) and 29 participants in the control group (CG; age: 59±12, 59% female), were included in the analysis. The baseline characteristics of both groups were comparable, except participants of IG were younger. On average, the PSL at baseline was low in both groups (IG: 9.7 ±5.4 points; CG: 8.5 ±6.9 points; p=.165), but 22% (n =15) in the IG and 20% (n =6) in the CG reported a high PSL. Most participants reported irregularities in CAR sampling, eg interruption of sleep (IG: 80% CG: 81%). After 8 weeks, most CAR parameters and the PSL decreased in the IG and CG, resulting in no differences of change between the groups. In the IG only, a decrease of PSL was linked to an increase of CAR parameters, eg AUCI (correlation coefficient =−0.307; p =.017). Conclusion: The HLCP may potentially reduce PSL and change the CAR, but results cannot be clearly attributed to the programme. Methodological challenges and multiple confounders, limit suitability of the CAR in the context of lifestyle interventions. Other measures (eg hair-cortisol) may give further insights. Trial registration: German Clinical Trials Register (DRKS); DRKS00018821; www.drks.d

Tu1086 Teaching Sonography in a Curricular Course During Undergraduate Medical Education: A Prospective Pilot Study

Heinzow H, Friederichs H, Lenz P, et al. Tu1086 Teaching Sonography in a Curricular Course During Undergraduate Medical Education: A Prospective Pilot Study. Gastroenterology. 2012;142(5):S-742-S-743

Successful treatment of oral Crohn's disease by anti-TNF-alpha dose escalation - a case report

Abstract Background Crohn’s Disease (CD) is typically characterized by abdominal symptoms, however, besides gastrointestinal symptoms, CD patients may suffer from extraintestinal manifestations which are far less common and medical treatment can be challenging. Case presentation We report about a 34-year-old Crohn’s Disease (CD) patient in clinical remission under adalimumab therapy who presented in the clinic for Cranio-Maxillo Surgery due to severe pain in the mandibular area. Ulcerative lesions of the buccal-side mucosa of the right mandible were detected. To rule out malignancy, a biopsy was obtained and revealed ulcerative stomatitis with noncaseating granulomas consistent with oral CD. Shortening the adalimumab administration interval to weekly injections resulted in a complete healing of the oral CD lesions without residual inflammation. Conclusion The case presented here demonstrates that gastroenterologists should evaluate and consider oral CD lesions as a possible marker of disease activity in patients despite having quiescent intestinal CD

Teaching ultrasound in a curricular course according to certified EFSUMB standards during undergraduate medical education: a prospective study

Heinzow HS, Friederichs H, Lenz P, et al. Teaching ultrasound in a curricular course according to certified EFSUMB standards during undergraduate medical education: a prospective study. BMC Medical Education. 2013;13(1): 84

Continuous synthesis of γ–valerolactone in a trickle-bed reactor over supported nickel catalysts

Various Ni-based catalysts were tested in the continuous liquid phase hydrogenation of levulinic acid (LA) to γ-valerolactone (GVL) in a trickle-bed reactor using water as solvent with the aim to develop an economic and environmentally friendly way for the GVL synthesis. For this purpose, various synthesis methods were used to prepare Ni-based catalysts, which were first screened in batch reactors. Characterization by X-ray diffraction, temperature-programmed reduction, electron microscopy, hydrogen chemisorption, and X-ray absorption spectroscopy showed that slow precipitation using urea resulted in a good Ni dispersion. The dispersion also improved at lower Ni loading, and smaller Ni particles mostly showed an enhanced catalytic performance for the synthesis of GVL. 5 wt % Ni/Al2O3 prepared by wet impregnation showed the highest specific activity for the hydrogenation of LA to GVL (90% LA conversion and 75% GVL yield) featuring an average Ni particle size of 6 nm. Some deactivation of the catalysts was observed, probably due to transformation of γ-Al2O3 to boehmite and sintering of the Ni particles. In addition, reoxidation of Ni particles may additionally lead to deactivation as concluded by comparison with screening studies in batch reactors