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Between the end of September and early October 2017, 106Ru was recorded by air monitoring stations across parts of Europe. In the environment, this purely anthropogenic radionuclide can be detected very rarely only. As far as known, 106Ru is only used in radiotherapy and possibly in radiothermal generators. Therefore, the episode drew considerable interest in the monitoring community, although the activity concentrations and resulting exposure were far below radiological concern. Health consequences can be practically excluded except possibly near the source. 106Ru in aerosols could be detected for several weeks and in some regions of Central and Eastern Europe tens, up to over 100 mBq/m³ were measured as one-day means. Discussions about a possible source continue until today (early 2019). Atmospheric back-modelling led to trajectories likely originating in the Southern to Northern Ural region of Russia and possibly Northern Kazakhstan. Suspiciously, no other anthropogenic radionuclides have been observed alongside, except minute concentrations of comparatively short-lived 103Ru (half life 39 d vs. 376 d for 106Ru). Due to the absence of other anthropogenic radionuclides, a reactor accident can be excluded, although both Ru isotopes are fission products generated in nuclear reactors. The exposure resulting from 106Ru activity concentration in air exceeded 200 mBq × d/m³ in some parts of Central and Eastern Europe. This leads to inhalation doses of up to about 0.3 µSv regionally, assuming the radiologically most efficient speciation, lacking better information, and inhalation dose conversion factors from ICRP 119. We show an interpolated map of the dose distribution over parts of Europe where sufficient measurements are available to us. Overlaying population density, we give an estimate of collective dose. The opportunity is also used to give a short review of origin, properties and use of 106Ru, as well as of accidents which involved release of this radionuclide.

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Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.

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It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51-mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations.

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DNA lesions resulting from impaired progression of replication forks are implicated in genetic instability and tumorigenesis. Because the cellular response to these lesions poses an important tumorigenesis barrier, the responsible signalling and repair pathways are often mutated or inactive in tumours. Here, we discuss how such deficiencies can in turn be exploited for cancer therapy.

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Poly(ADP-ribosyl)ation of proteins is involved in the regulation of basal cellular processes and seems to be crucial for genomic integrity and cell survival. Several nuclear poly(ADP-ribose) polymerases (PARPs) are known which interact with various proteins involved in DNA metabolism. These proteins can be targets of poly(ADP-ribosyl)ation, which generally downregulates their activities. Accordingly, PARPs have been implicated in numerous processes involving chromosomal DNA, such as the regulation of chromatin structure, DNA repair, replication and transcription. PARP-1, the major cellular PARP, and PARP-2 are activated by DNA strand breaks. These enzymes have been shown to participate in DNA repair. PARP-1 has also been associated with DNA replication and recombination. Another outstanding feature of PARP-1 is its impact on the activities of transcription factors and on gene expression. Two other nuclear PARP enzymes, tankyrase-1 and tankyrase-2, are important for telomere maintenance.

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OBJECTIVE: To create a statistical model using three-dimensional (3D) head kinematics and range of motion (ROM) to distinguish between people with whiplash syndrome and asymptomatic controls. STUDY DESIGN: Cross-sectional study to estimate validity of diagnostic measures. METHODS: Fifty-one asymptomatic controls (most of whom were women), 18-35 yr old and 30 matched whiplash trauma patients seeking care from suburban outpatient clinics were sought. 3D kinematic parameters of head motion were obtained during tracking tasks (e.g., flexion, extension, etc.) and cervical ROM was measured via a head mounted inclinometer. Their level of pain and disability was assessed via a self-administered neck disability index questionnaire and visual analog pain scale (VAS). RESULTS: A scoring system of biomechanical abnormalities derived from the vertical piercing point, its second derivative and symmetry during oblique tasks. The scores ranged from a minimum of 0 to a maximum of 3. A cutoff of > or = 0.5 correctly identified the greatest number of subjects and minimized false positives (sensitivity 77%, specificity 82%, likelihood ratio 4.5). ROM performed similarly well at a cutoff of 1 SD below the normative mean (sensitivity 77%, specificity 84%, likelihood ratio 3.9). CONCLUSIONS: There is potential for biomechanical analysis to objectively detect abnormalities. The statistical model yielded moderate to high sensitivity and specificity using 3D helical-axis parameters of the head and standard ROM. The model development will continue via this process in future studies. These data could be a first step toward the creation of useful, noninvasive protocols for the diagnosis and management of soft tissue trauma of the neck.

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OBJECTIVE: To evaluate diagnostic and biomechanical correlates and treatment outcomes of manipulative/adjustive care in patients highly selected for sacroiliac joint syndrome (SIJS). DESIGN: Descriptive case series, 1 wk baseline, 1 yr follow-up. SETTING: Private chiropractic practice. PATIENTS: Ten out of 153 consecutive new patients (4 male and 6 female) with "primary," chronic, uncomplicated SIJS were selected over an 11-mo period on the basis of painful SIJ and provocation tests. MAIN OUTCOME MEASURES: Back pain (visual analogue scale), Oswestry disability index, lumbar provocation tests and biomechanical measures of gait and postural sway. INTERVENTION: Six-wk regimen of mechanical force, manually assisted, short lever adjustments (MFMA) with an Activator instrument. RESULTS: Pain decreased significantly from a mean baseline value of 25 to 12 (t = 2.28; p < .05). Likewise, the average disability scores diminished from 28 to 13% (t = 2.3; p < .05), and a reduction in the number of positive provocation tests was noted (Fisher Exact Probability range Z = 0.025-0.045). Gait and sway parameters were indistinguishable from normals, before or after treatment. Response to the 1-yr follow-up questionnaire (6/10) revealed stability of symptoms at a low level. CONCLUSIONS: While the majority of subjects recorded some degree of positive outcome, we conclude that: a) discrete SIJS remains difficult to diagnose, but may be possible by judicious choice of screening tests; b) MFMA may benefit some patients with chronic SIJ pain; and c) gait and sway measurement yielded no correlation with clinical conditions.

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