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DQPB is software for calculating U-Pb ages while accounting for the effects of radioactive disequilibrium among intermediate nuclides of the U-series decay chains. The software is written in Python and distributed both as a pure Python package, and a stand-alone GUI application that integrates with standard Microsoft Excel spreadsheets. The software implements disequilibrium U-Pb equations to compute ages using various approaches, including concordia-intercept ages on a Tera-Wasserburg diagram, disequilibrium U-Pb isochron ages, Pb/U ages based on single analyses, and modified 207Pb ages. These age calculation approaches are tailored toward young materials that cannot reasonably be assumed to have attained radioactive equilibrium at the time of analysis, although they may also be applied to older materials where disequilibrium is no longer analytically resolvable. The software allows users to implement a variety of regression algorithms using both classical and robust statistics approaches, compute weighted average ages, and construct customisable, publication-ready plots of U-Pb age data. Age uncertainties are propagated using Monte Carlo methods.

Background Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. Clinical trial identifier NCT02157792.

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

This essay will explore the origins of the cult and doctrine of Christ the King in the encyclicals of pope Pius XI and the role which the doctrine it played in his closely-twinned strategies of ‘a Christian restoration of society in a Catholic sense’ and the propaganda battles with the Church’s enemies, especially Communism, as the theological inspiration of Catholic lay mobilisation through the organisations of Catholic Action in the world-wide Church, from the early 1920s to the 1960s. Focussed on the use of the doctrine of Christus Rex as the key tool of Vatican apologetics against the enemies of the Roman Catholic Church, the essay will also show how it came to be exploited by more right-wing Catholic groups in the inter-war period, and how it has remained a major weapon in the armoury of traditionalist Catholics, as well as far right groups, down to the present day.

Students’ abilities to self-assess their understanding can influence their learning and academic performance. Different factors, such as performance level, have been shown to relate to student self-assessment. In this study, hierarchical linear modeling was used to identify factors and quantify their effects on the changes observed in chemistry students’ self-assessed understanding when engaging in instructional activity. This study replicates and expands on previous findings regarding performance by showing that the worse students performed on a task, the more likely they were to lower their self-assessed understanding after that activity. Task difficulty was found to be a significant effect on change in students' self assessments with students being more likely to lower their self-assessed understanding after a more difficult task and raise it following an easier task independent of performance. Perceived comparative understanding (how students thought they compared to their surrounding peers) was also found to be a significant effect. Students who later reported their understanding to be lower than their peers, as compared to those who later reported their understanding to be about the same as their peers, were observed to have lowered their self-assessed understanding. Actual comparative performance (difference in performance of the student to their surrounding peers), gender, and feedback were not found to be significant effects on change in students’ self-assessed understanding. The results of this investigation may inform instructors on how their instructional decisions differentially impact changes in students’ judgements about their understanding.

BackgroundBerzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.MethodsAdult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).ResultsThirty-one patients received berzosertib (90–210 mg/m2) and cisplatin (40–75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2(days 2 and 9) and cisplatin 75 mg/m2(day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.ConclusionsBerzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting.Clinical Trials IdentifierNCT02157792.

The stagnation of the Northern Irish market immediately stands out in marked contrast to the doubling of the Republic's visitor total. Visitors to Ireland are representatives of a public that quickly became all too aware of the blacker side of Irish affairs through a media coverage that reached saturation point. Surveys are conducted regularly by both Bord Failte and the Northern Irish Tourist Board eliciting, inter alia, information on the attractions to holidaymakers and their usage of various products. The ice and water that have acted as agents of erosion and deposition in the moulding of the Irish landscape have also presented a series of more specific resources for tourist exploitation through activity-based holidays. In coastal areas a high proportion of superior quality fine sand beaches washed by clean Atlantic waters provide a superior resource in comparison to the littoral on the other side of the Irish Sea.

IntroductionHypoglycaemia is a frequent adverse event and major barrier for achieving optimal blood glucose levels in people with type 1 or type 2 diabetes using insulin. The Hypo-RESOLVE (Hypoglycaemia—Redefining SOLutions for better liVEs) consortium aims to further our understanding of the day-to-day impact of hypoglycaemia. The Hypo-METRICS (Hypoglycaemia—MEasurement, ThResholds and ImpaCtS) application (app) is a novel app for smartphones. This app is developed as part of the Hypo-RESOLVE project, using ecological momentary assessment methods that will minimise recall bias and allow for robust investigation of the day-to-day impact of hypoglycaemia. In this paper, the development and planned psychometric analyses of the app are described.Methods and analysisThe three phases of development of the Hypo-METRICS app are: (1) establish a working group—comprising diabetologists, psychologists and people with diabetes—to define the problem and identify relevant areas of daily functioning; (2) develop app items, with user-testing, and implement into the app platform; and (3) plan a large-scale, multicountry study including interviews with users and psychometric validation. The app includes 7 modules (29 unique items) assessing: self-report of hypoglycaemic episodes (during the day and night, respectively), sleep quality, well-being/cognitive function, social interactions, fear of hypoglycaemia/hyperglycaemia and work/productivity. The app is designed for use within three fixed time intervals per day (morning, afternoon and evening). The first version was released mid-2020 for use (in conjunction with continuous glucose monitoring and activity tracking) in the Hypo-METRICS study; an international observational longitudinal study. As part of this study, semistructured user-experience interviews and psychometric analyses will be conducted.Ethics and disseminationUse of the novel Hypo-METRICS app in a multicountry clinical study has received ethical approval in each of the five countries involved (Oxford B Research Ethics Committee, CMO Region Arnhem-Nijmegen, Ethikkommission der Medizinischen Universität Graz, Videnskabsetisk Komite for Region Hovedstaden and the Comite Die Protection Des Personnes SUD Mediterranne IV). The results from the study will be published in peer review journals and presented at national and international conferences.Trial registration numberNCT04304963.

Background: ATR is a critical regulator of the cellular response to replication stress; it signals DNA damage repair, mediated through homologous recombination. Many cancers depend on ATR to survive DNA damage. M6620 is a potent, selective inhibitor of ATR that augments the anticancer activity of cisplatin in preclinical triple-negative breast cancer (TNBC) models. Given the high prevalence of TP53 mutations in TNBC and limited platinum responsiveness in patients lacking a BRCA1/2 mutation, this study was designed to evaluate the safety and efficacy of M6620 in combination with cisplatin in an expansion cohort of patients with BRCA1/2 wild-type advanced/metastatic TNBC. Methods: Eligible patients had advanced/metastatic ER-, PR-, and HER2- breast cancer with 0-2 prior non–platinum-based therapies and measurable disease per RECIST 1.1. First line patients were eligible if relapse occurred ≥3 months after prior (neo)adjuvant chemotherapy. Of a maximum 50 patients planned for enrollment, ≥30 were required to have BRCA1/2 germline wild-type status and basaloid molecular subtype tumors on central testing. Patients received intravenous cisplatin 75 mg/m2 on day 1 with intravenous M6620 140 mg/m2 on days 2 and 9 of each 21-day cycle. In patients intolerant of cisplatin or at investigator's discretion, cisplatin could be switched to carboplatin AUC 5 with M6620 90 mg/m2. Results: At the time of abstract submission, 35 female patients were enrolled in this study; 18 patients with confirmed BRCA1/2 wild-type and basaloid metastatic TNBC who received ≥1 cycle of study drug and had ≥1 baseline scan and ≥1 on-treatment scan at the time of the data cut were included in the primary efficacy analysis. Median progression-free survival (PFS) was 4.1 months (90% CI, 1.6-6.9 months). PFS was ≥ 6 months in 2 patients and ≥ 3 months in 8 patients. Preliminary unconfirmed objective response [complete response or partial response (PR)] was observed in 38.9% (90% CI, 19.9%-60.8%) of patients. All 7 patients with preliminary objective response had PR as best overall response; the longest duration of response was 183 days. Response was ongoing in 4 patients with PR at the time of data cutoff. Grade ≥3 related treatment-emergent adverse events occurred in 16 of 35 patients: neutropenia (n=8), anemia (n=5), vomiting (n=4), nausea (n=3), and, in 1 patient each, thrombocytopenia, neutrophil count decreased, platelet count decreased, hypokalemia, generalized weakness, rigors, and acute kidney injury. Conclusions: Combination of M6620 and cisplatin shows encouraging antitumor activity and tolerability in patients with advanced/metastatic TNBC. The study is ongoing; updated safety and efficacy results will be presented. Citation Format: Telli ML, Lord S, Dean E, Abramson V, Arkenau H-T, Murias C, Becerra C, Tang R, Penney MS, Pollard J, Conboy G, Fields SZ, Shapiro G, Tolaney SM. ATR inhibitor M6620 (formerly VX-970) with cisplatin in metastatic triple-negative breast cancer: Preliminary results from a phase 1 dose expansion cohort (NCT02157792) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-07.

Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4-amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered-binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs.

Calls for educational reform in undergraduate STEM education have become more prominent in recent years, particularly in introductory/foundational courses. Such reform efforts were initiated 10 years ago in the general chemistry program at the University of Arizona. In this contribution, we describe the major successes and challenges encountered during the full implementation of a new chemical thinking curriculum across all sections of a large course serving thousands of science and engineering majors every year. Besides describing the goals and structure of the alternative curriculum, as well as its impact on student learning, our work seeks to provide insights into institutional conditions, resources, and constraints that foster or hinder the success of major educational reforms.

Objective In this study, we develop and apply a high-throughput screening protocol to investigate the activity of non-ionic surfactants, with a broad range of hydrophilic–lipophilic balance values, against ABCB1-mediated efflux transport and ABCC2-mediated efflux transport. Methods Caco-2 cells were grown for 7 days in 96-well plates, then washed and incubated with the test materials for 2 h in the presence of 2.5 μm of either rhodamine 123 (R-123) or 5(6)-Carboxy-2′,7′ dichlorofluorescein diacetate as probes of ABCB1 and ABCC2, respectively. Key findings Of the surfactants tested, no activity against ABCC2 was detected and all surfactants showing efficacy against ABCB1 had a HLB value of 22 or below. Inhibition of ABCB1 was seen in the order of efficacy to be poloxamer 335 > poloxamer 40 > Crovol A-70 > Myrj S-40 > poloxamer 184 > poloxamer 182 > Etocas 40 > Tween 20 > Etocas 29 > Tween 80 > Acconon C-44 > Span 20. With regard to this inhibition, the distribution of hydrophilic regions is more important than the HLB value. Conclusion This work demonstrates a high-throughput protocol for detecting materials that can modulate ABCB1-mediated efflux. These surfactants could be exploited to improve oral delivery of drugs prone to efflux.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Groups of racist skinheads now constitute a significant element of the global radical right. The British youth subculture of the late 1960s has thus been transformed into a worldwide social movement, the violent cutting-edge of white supremacist resistance to multiculturalism. Pollard examines the historical development of the racist skinhead phenomenon and, in particular, analyses the origins, nature and development of the ideas that inspire it: the foundational myth; ‘skinhead, a way of life’; Odinism or paganism; the skinhead as victim; skinheads as a vanguard of white, male, working-class revolutionaries; National Socialism and antisemitism; and, above all, racialism.

The essays brought together here were originally delivered as presentations at the ‘Fascist Ideologues: Past and Present’ conference, held at Teesside University in July 2013. The collection addres...

There is limited research within the UK investigating the effects of shift work on paramedics. Paramedics have relatively high rates of sickness levels and there are links between shift work and health. This study explores UK paramedics’ perceptions of the impact of working shifts. Methods: Exploratory qualitative research was utilised to investigate the perceptions of UK paramedics on the impacts of working shifts. Two focus groups were completed involving 11 paramedics. The transcriptions were analysed using thematic analysis. Results: Paramedics described factors associated with working shifts that mirror research already completed within different occupations: effects on physical health, fatigue, family life, safety and performance; but paramedics additionally described factors that are more limited to working in the paramedic profession such as a broader range of psychological stressors and organisational factors. The theme of psychological health was a wider theme that went beyond shift work and encompassed the overall paramedic role and the unique and stressful nature of the work. Conclusions: This research has allowed an insight into the perceived effects of shift work on UK paramedics and exposes the challenges paramedics face in their working environment. There is a suggested link between the relatively high rates of sickness and the effects of shift work and paramedics’ overall working environment. Further exploration and recognition of the effects of shift work on UK paramedics is recommended.

Existentialism and Depressive Realism (DR) share some important concerns, most notably meaninglessness, absurdity, death, self-deception and free will/freedom. Within existential philosophy and therapy there is an understanding of the difficult givens of being human. However, because these difficulties relate to our freedom and possibilities, existentialism, unlike DR, can offer a positive and hopeful response. Unlike DR, most of which seems to affirm an essentialist view of ‘truth’ and ‘reality’, existentialism prioritizes our ‘way’ of ‘being’ over an essential human nature, which leads to an openness to individual human experience, likely to include positive elements.

The opening of the papers of pope Pius XI (1922‑1939) in the Vatican Archives in 2006 inevitably provoked a veritable ‘explosion’ of conferences and studies of the pontificate of that pope – monographs, journal articles and edited collections. Some historians like Emma Fattorini with her book Pio XI, Mussolini e Hitler (Milan, 2007) and David I. Kertzer, The Pope and Mussolini : The Secret History of Pius XI and the Rise of Fascism in Europe (New York, 2014) have focussed on papa Ratti himsel...

Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo- and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo- and radiosensitisation by ATR inhibition, the lack of chemo- or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy.

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

ATR is a highly versatile player in the DNA damage response (DDR) that signals DNA damage via CHK1 phosphorylation to the S and G2/M cell cycle checkpoints and to promote DNA repair. It is activated by ssDNA, principally occurring due to replication stress that is caused by unrepaired endogenous DNA damage or induced by a variety of anticancer chemotherapy and ionizing radiation. Since an almost ubiquitous feature of cancer cells is loss of G1 control, e.g., through p53 mutation, it is thought that their greater dependence on S and G2/M checkpoint function may render them more susceptible to ATR inhibition. ATR promotes homologous recombination DNA repair and inter-strand cross-link repair. Impairment of ATR function by genetic means or with inhibitors increases the sensitivity of cells to a wide variety of DNA damaging chemotherapy and radiotherapy, with the greatest sensitization observed with gemcitabine and cisplatin. Early inhibitors developed in the 1990s were weak and non-specific but the encouraging data led to the development of more potent and specific inhibitors. We review here the pre-clinical chemo- and radiosensitisation data obtained with these inhibitors that has led to the entry into clinical trial, the potential to combine ATR inhibitors with other DNA repair modulators, and identification of single-agent ATR inhibitor cytotoxicity in cells with activated oncogenes and particular defects in the DDR that may result in greater replication stress or dependence on ATR for survival.

The election of Giacomo Della Chiesa as Pope Benedict XV coincided with the outbreak of the First World War. His pacifism led to vigorous attempts to halt the war, which failed because of the Vatican's isolation and poor diplomatic prestige. The most notable attempt was Benedict Peace Note of 1917 that set out seven proposals for negotiating peace. Despite Benedict's failure to alter the course of the war, his diplomatic efforts were matched by humanitarian action on behalf of prisoners of war and famished children. Benedict's legacy has been greater diplomatic resources for the Vatican and an energetic search for peace.

Roger Griffin has famously defined the essence of inter-war European fascisms as 'a form of palingenetic, populist ultra-nationalism'. The origins of Catholic corporatist ideas are to be found in counter-revolutionary thought as it developed in Catholic circles in Austria in the mid to late nineteenth century. The critical milestone in the development of Catholic social theory and activism was the publication of Pope Leo XIII's encyclical Rerum Novarum. Rerum Novarum was heavily dependent upon a neo-Thomist philosophical frame, which Leo promoted throughout his reign as the Catholic philosophy par excellence. The papal silence on the question of corporatism did not, however, prevent it from becoming a topic of discussion in the Catholic political parties that emerged in the aftermath of the First World War. The chief author of Quadragesimo Anno, Fr Nell-Breuning was critical of the 'authoritarian, Christian state with a corporatist base' which Dollfuss established in Austria in the wake of the civil war with the Viennese Socialists.

Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10–15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3′-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640–1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.

The protein kinase ataxia telangiectasia mutated and Rad3-related ATR is one of the key mediators of the DNA damage response. ATR is recruited to regions of single-stranded DNA, which most commonly arise during replication stress (RS). RS occurs during S-phase when the cell’s DNA replication machinery encounters problems such as unresolved DNA lesions. In addition, treatment of cells with DNA-damaging agents can lead to RS as cells progress to S-phase without resolving damage incurred by such agents. Elevated levels of RS are evident in some cancer cells, even in the absence of a DNA-damaging agent resulting from expression of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways. RS in cancer cells can drive reliance on ATR for survival and, accordingly, ATR inhibitors may have benefit as monotherapy. M4344 was determined to be an adenosine triphosphate (ATP)-competitive, highly potent, and tight-binding inhibitor of ATR with a Ki of < 150 pM. Minimal inhibitory activity was observed against a large panel of unrelated protein kinases, with 308 of 312 kinases tested having a measured Ki corresponding to more than 100-fold selectivity. M4344 potently inhibits ATR-driven phosphorylated checkpoint kinase-1 (P-Chk1) phosphorylation with an IC50 of 8 nM. Profiling on a selected set of cancer cell lines showed synergy with several types of DNA damaging chemotherapeutics as well as PARP1/2 and CHK1 inhibitors. In monotherapy efficacy studies M4344 showed tumor stasis to regression in tumor models with alternative lengthening of telomeres (ALT). In combination with PARP inhibitors, tumor regression could be observed in triple-negative breast cancer xenograft models. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing. Citation Format: Frank T. Zenke, Astrid Zimmermann, Heike Dahmen, Brian Elenbaas, John Pollard, Philip Reaper, S Bagrodia, M E. Spilker, C Amendt, Andree Blaukat. Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 369.