Electrochemical, plasma and synthetic studies of dithiadiazolium and related compounds

The crystal structure of [PhCNSSN] AsF(_6) and (MeCSSN)(_2) have been determined and a variety of new 1,2 and 1,3 dithiadiazolium derivatives synthesised including [CH(_3)CH(_2)CH(_2) CNSSN]C1 and[(CH(_3)(_3)CCNSSN]C1. [PhCN(_2)S(_2)] AsF(_6) has a longer S-S bond compared to [PhCN(_2)S(_2)]C1 and has provided an insight into the molecular bonding in the three centre interactions in the latter. The crystalline methyldithiadiazole contains planar CNSSN rings. Within the dimer unit parallel monomer rings are linked via one weak S...S bond. Enthalpies of fusion for a number of dithiadiazole derivatives were measured and found to be similar but significantly greater than for organic molecules of similar molecular weight. This together with the reduction of [CH(_3)CH(_2)CH(_2)CN(_2)S(_2)]CI and [(CH(_3))(_3)CCN(_2)S(_2)]C1 which gave new paramagnetic liquids has led to a more detailed understanding of the bonding and structure in these ring systems. Dimeric aryldithiadiazoles (RCNSSN)(_2) (R = Ph or p – C1Ph) were treated with atomic nitrogen, generated in a cool DC plasma, to form the corresponding dithiatriazine dimers by nitrogen insertion into the S-S bond; Alkyl derivatives (R = Me, propyl, bu(^t)) gave polymeric products. Dithiadiazolium salts [RCNSSN](^+)X(^-) (R = Ph, p-ClPh), X = Br, I, CN or S(_3)N(_3)) also reacted with nitrogen plasma to give high yields of the respective dithiatriazine. Structural criteria for these reactions are discussed. The electrochemistry of (RCNSSN)(_2), (RCNSSN)(_2), [RCNSSN]X (X=C1- or AsF(_6)(^-) and [RCNSNS] AsF(_6) (R= Ph,p-C1Ph,p-CH3Ph,p-CNPh,anthracene,Me, propyl,bu(^t),C1(_3)C, CF(_3)) were studied by cyclic voltammetry.A new S(_2)N(^+ )salt, S(_2)NCF(_3)SO(_3), was synthesised from the reaction of AgCF(_3)SO(_3) with (NSC1)(_3) and sulphur in liquid SO(_2) and its usefulness as a reagent compared to S(_2)NAsF(_6) and S(_2)NSbC1(_6). The crystal structure of S(_3)N(_2)CF(_3)SO(_3) was determined, crystals of which were isolated from the same reaction mixture and an equilibrium between S(_2)N(^+),SN(^+) and S(_3)N(_2)(^+)(^.) postulated

Sustained water storage in Horn of Africa drylands dominated by seasonal rainfall extremes

Rural communities in the Horn of Africa Drylands (HAD) are increasingly vulnerable to multi-season droughts due to the strong dependence of livelihoods on seasonal rainfall. We analysed multiple observational rainfall datasets for recent decadal trends in mean and extreme seasonal rainfall, as well as satellite-derived terrestrial water storage and soil moisture trends arising from two key rainfall seasons across various subregions of HAD. We show that, despite decreases in total March-April-May rainfall, total water storage in the HAD has increased. This trend correlates strongly with seasonal totals and especially with extreme rainfall in the two dominant HAD rainy seasons between 2003 and 2016. We further show that high-intensity October-November-December rainfall associated with positive Indian Ocean Dipole events lead to the largest seasonal increases in water storage that persist over multiple years. These findings suggest that developing groundwater resources in HAD could offset or mitigate the impacts of increasingly common droughts

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Broad Down, Devon: archaeological and other stories

publication-status: PublishedThis is a post-print, author-produced version of an article accepted for publication Journal of Material Culture, 2010, Vol. 15, Issue 3, pp. 345 - 367. Copyright © 2010 SAGE Publications. The definitive publisher-authenticated version is available online at http://mcu.sagepub.com/content/15/3/345.shortThis article explores the knowledge construction process of an archaeological site in East Devon, UK. Bouncing off an oral historical account of the site that seems to run against scientific truth claims, the author investigates the story of how knowledge of the site has developed over the last two centuries. Building on previous work that explores the history and practice of archaeology, the article opens up questions of what counts as evidence. Then, taking a cue from more recent work that suggests a more dynamic and open-ended engagement with the landscape, the article turns to examine how the meaning of a site can be made and remade. As part of this endeavour, questions of what as well as who can ‘speak’ are examined and some space is opened up for the agency of ‘minor figures’, both human and non-human

Planetary science and exploration in the deep subsurface: results from the MINAR Program, Boulby Mine, UK

The subsurface exploration of other planetary bodies can be used to unravel their geological history and assess their habitability. On Mars in particular, present-day habitable conditions may be restricted to the subsurface. Using a deep subsurface mine, we carried out a program of extraterrestrial analog research – MINe Analog Research (MINAR). MINAR aims to carry out the scientific study of the deep subsurface and test instrumentation designed for planetary surface exploration by investigating deep subsurface geology, whilst establishing the potential this technology has to be transferred into the mining industry. An integrated multi-instrument suite was used to investigate samples of representative evaporite minerals from a subsurface Permian evaporite sequence, in particular to assess mineral and elemental variations which provide small-scale regions of enhanced habitability. The instruments used were the Panoramic Camera emulator, Close-Up Imager, Raman spectrometer, Small Planetary Linear Impulse Tool, Ultrasonic drill and handheld X-ray diffraction (XRD). We present science results from the analog research and show that these instruments can be used to investigate in situ the geological context and mineralogical variations of a deep subsurface environment, and thus habitability, from millimetre to metre scales. We also show that these instruments are complementary. For example, the identification of primary evaporite minerals such as NaCl and KCl, which are difficult to detect by portable Raman spectrometers, can be accomplished with XRD. By contrast, Raman is highly effective at locating and detecting mineral inclusions in primary evaporite minerals. MINAR demonstrates the effective use of a deep subsurface environment for planetary instrument development, understanding the habitability of extreme deep subsurface environments on Earth and other planetary bodies, and advancing the use of space technology in economic mining

A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma

BACKGROUND ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. METHODS We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. RESULTS A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. CONCLUSION This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BACKGROUND Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. METHODS Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. In all patients, the 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with Grade 3-4 in 3 patients. No new safety signals were identified. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.info:eu-repo/semantics/publishedVersio