Reinterpreting the age of the uppermost ‘Old Red Sandstone’ and Early Carboniferous in Scotland

In Scotland, the base of the Ballagan Formation has traditionally been placed at the first grey mudstone within a contiguous Late Devonian to Carboniferous succession. This convention places the Devonian–Carboniferous boundary within the Old Red Sandstone (ORS) Kinnesswood Formation. The consequences of this placement are that tetrapods from the Ballagan Formation were dated as late Tournaisian in age and that the ranges of typically Devonian fish found in the Kinnesswood Formation continued into the Carboniferous. The Pease Bay specimen of the fish Remigolepis is from the Kinnesswood Formation. Comparisons with its range in Greenland, calibrated against spores, show it was Famennian in age. Detailed palynological sampling at Burnmouth from the base of the Ballagan Formation proves that the early Tournaisian spore zones (VI and HD plus Cl 1) are present. The Schopfites species that occurs through most of the succession is Schopfites delicatus rather than Schopfites claviger. The latter species defines the late Tournaisian CM spore zone. The first spore assemblage that has been found in Upper ‘ORS' strata underlying the Ballagan Formation (Preston, Whiteadder Water), contains Retispora lepidophyta and is from the early latest Famennian LL spore zone. The spore samples are interbedded with volcaniclastic debris, which shows that the Kelso Volcanic Formation is, in part, early latest Famennian in age. These findings demonstrate that the Ballagan Formation includes most of the Tournaisian with the Devonian–Carboniferous boundary positioned close to the top of the Kinnesswood Formation. The Stage 6 calcrete at Pease Bay can be correlated to the equivalent section at Carham, showing that it represents a time gap equivalent to the latest Famennian glaciation(s). Importantly, some of the recently described Ballagan Formation tetrapods are older than previously dated and now fill the key early part of Romer's Gap

The terrestrial landscapes of tetrapod evolution in earliest Carboniferous seasonal wetlands of SE Scotland

The Lower Mississippian (Tournaisian) Ballagan Formation in SE Scotland yields tetrapod fossils that provide fresh insights into the critical period when these animals first moved onto land. The key to understanding the palaeoenvironments where they lived is a detailed analysis of the sedimentary architecture of this formation, one of the thickest and most completely documented examples of a coastal floodplain and marginal marine succession from this important transitional time anywhere in the world. Palaeosols are abundant, providing a unique insight into the early Carboniferous habitats and climate. More than 200 separate palaeosols are described from three sections through the formation. The palaeosols range in thickness from 0.02 to 1.85 m and are diverse: most are Entisols and Inceptisols (63%), indicating relatively brief periods of soil development. Gleyed Inseptisols and Vertisols are less common (37%). Vertisols are the thickest palaeosols (up to 185 cm) in the Ballagan Formation and have common vertic cracks. Roots are abundant through all the palaeosols, from shallow mats and thin hair-like traces to sporadic thicker root traces typical of arborescent lycopods. Geochemical, isotope and clay mineralogical analyses of the palaeosols indicate a range in soil alkalinity and amount of water logging. Estimates of mean annual rainfall from palaeosol compositions are 1000 –1500 mm per year. The high mean annual rainfall and variable soil alkalinities contrast markedly with dry periods that developed deep penetrating cracks and evaporite deposits. It is concluded that during the early Carboniferous, this region experienced a sharply contrasting seasonal climate and that the floodplain hosted a mosaic of closely juxtaposed but distinct habitats in which the tetrapods lived. The diversification of coastal floodplain environments identified here may link to the evolution and movement of tetrapods into the terrestrial realm

A new Mississippian tetrapod from Fife, Scotland, and its environmental context

The Visean stage of the Mississippian was a time of rapid tetrapod diversification which marks the earliest appearance of temnospondyls, microsaurs and the limbless aïstopods. Tetrapod finds from this stage are very rare and only a dozen sites are known worldwide. Here we announce the discovery of a new Visean site in Fife, Scotland, of Asbian age, and from it describe a new species of the baphetoid Spathicephalus. These specimens represent the oldest known baphetoid by three million years, yet belong to the most specialized members of the clade. Unlike typical baphetoids with large marginal teeth and palatal fangs characteristic of early tetrapods, spathicephalids had very broad flattened heads with a dentition consisting of a large number of small, uniform teeth. Spathicephalids were probably one of the earliest tetrapod groups to use suction feeding on small, aquatic prey. Palynological and sedimentological analysis indicates that the new fossil bed was deposited in a large, stratified, freshwater lake that became increasingly saline

A Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) in Patients with Metastatic Melanoma

Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naïve (previously untreated) and previously treated patients with metastatic melanoma.Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea.Ixabepilone has no meaningful activity in either chemotherapy-naïve (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted.Clinical Trials.gov NCT00036764

Sensitive droplet digital PCR method for detection of TERT promoter mutations in cell free DNA from patients with metastatic melanoma

Background: Currently mainly BRAF mutant circulating tumor DNA (ctDNA) is utilized to monitor patients with melanoma. TERT promoter mutations are common in various cancers and found in up to 70% of melanomas, including half of BRAF wildtype cases. Therefore, a sensitive method for detection of TERT promoter mutations would increase the number of patients that could be monitored through ctDNA analysis. Methods: A droplet digital PCR (ddPCR) assay was designed for the concurrent detection of chr5:1,295,228 C \u3e T and chr5:1,295,250 C \u3e T TERT promoter mutations. The assay was validated using 39 melanoma cell lines and 22 matched plasma and tumor samples. In addition, plasma samples from 56 metastatic melanoma patients and 56 healthy controls were tested for TERT promoter mutations. Results: The established ddPCR assay detected TERT promoter mutations with a lower limit of detection (LOD) of 0.17%. Total concordance was demonstrated between ddPCR and Sanger sequencing in all cell lines except one, which carried a second mutation within the probe binding-site. Concordance between matched plasma and tumor tissue was 68% (15/22), with a sensitivity of 53% (95% CI, 27%- 79%) and a specificity of 100% (95% CI, 59%-100%). A significantly longer PFS (p=0.028) was evident in ctDNA negative patients. Importantly, our TERT promoter mutations ddPCR assay allowed detection of ctDNA in 11 BRAF wild-type cases. Conclusions: The TERT promoter mutation ddPCR assay offers a sensitive test for molecular analysis of melanoma tumors and ctDNA, with the potential to be applied to other cancers

Palaeogeography of tropical seasonal coastal wetlands in northern Britain during the early Mississippian Romer's Gap

The lower Mississippian Ballagan Formation of northern Britain is one of only two successions worldwide to yield the earliest known tetrapods with terrestrial capability following the end-Devonian mass extinction event. Studies of the sedimentary environments and habitats in which these beasts lived have been an integral part of a major research project into how, why and under what circumstances this profound step in the evolution of life on Earth occurred. Here, a new palaeogeographic map is constructed from outcrop data integrated with new and archived borehole material. The map shows the extent of a very low-relief coastal wetland developed along the tropical southern continental margin of Laurussia. Coastal floodplains in the Midland Valley and Tweed basins were separated from the marginal marine seaway of the Northumberland–Solway Basin to the south by an archipelago of more elevated areas. A complex mosaic of sedimentary environments was juxtaposed, and included fresh and brackish to saline and hypersaline lakes, a diverse suite of floodplain palaeosols and a persistent fluvial system in the east of the region. The strongly seasonal climate led to the formation of evaporite deposits alternating with flooding events, both meteoric and marine. Storm surges drove marine floods from the SW into both the western Midland Valley and Northumberland–Solway Basin; marine water also flooded into the Tweed Basin and Tayside in the east. The Ballagan Formation is a rare example in the geological record of a tropical, seasonal coastal wetland that contains abundant, small-scale evaporite deposits. The diverse sedimentary environments and palaeosol types indicate a network of different terrestrial and aquatic habitats in which the tetrapods lived

Early Mississippian evaporites of coastal tropical wetlands

Extensive evaporites in Lower Mississippian successions from palaeoequatorial regions are commonly used as evidence for an arid to semi‐arid palaeoclimate. However, in this article, detailed studies of evaporites and their context refute this interpretation. Detailed sedimentological and petrographical analysis of the Lower Mississippian of northern Britain, is combined with archived log data from more than 40 boreholes across southern Scotland, northern England and Northern Ireland, and published literature from Canada. Two key cores from the Tweed Basin and the northern margin of the Northumberland – Solway Basin contain 178 evaporite intervals and reveal twelve distinct forms of gypsum and anhydrite across seven facies that are associated with planar laminated siltstone and intercalated thin beds of ferroan dolostone. Nodular gypsum and anhydrite, typically in intervals <1 to 2 m thick, are integral components of the succession. Nodular evaporite occurs within about 1 m of a palaeosurface, but most evaporite deposits represent ephemeral brine pans to semi‐permanent hypersaline lakes or salinas on a floodplain that was subjected periodically to storm surges introducing marine waters. Formation of evaporites under a strongly seasonal climate in a coastal wetland is supported by palaeosol types and geochemical proxies, and from palaeobotanical evidence published previously. Although 65% of modern equatorial areas experience a strongly seasonal climatic regime, salinas and sabkhas are a minor component today in comparison with the evidence from these Lower Mississippian successions. This implies that the earliest terrestrial environments were complex and dynamic, providing a diverse range of habitats in which the early tetrapods became terrestrialized and represent a setting that is rarely preserved in the geological record

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma

Publisher Copyright: © 2021, The Author(s).Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). Patients and methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1–617) and 71 days (range, 1–490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1–24.5) in the HNSCC cohort and 19% (90% CI, 9.2–32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7–4.7) and 1.9 months (95% CI, 1.7–3.7) in the HNSCC and NSCLC cohorts. Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.Peer reviewe

External validation and recalibration of an incidental meningioma prognostic model - IMPACT: protocol for an international multicentre retrospective cohort study.

INTRODUCTION: Due to the increased use of CT and MRI, the prevalence of incidental findings on brain scans is increasing. Meningioma, the most common primary brain tumour, is a frequently encountered incidental finding, with an estimated prevalence of 3/1000. The management of incidental meningioma varies widely with active clinical-radiological monitoring being the most accepted method by clinicians. Duration of monitoring and time intervals for assessment, however, are not well defined. To this end, we have recently developed a statistical model of progression risk based on single-centre retrospective data. The model Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and MRI Tests (IMPACT) employs baseline clinical and imaging features to categorise the patient with an incidental meningioma into one of three risk groups: low, medium and high risk with a proposed active monitoring strategy based on the risk and temporal trajectory of progression, accounting for actuarial life expectancy. The primary aim of this study is to assess the external validity of this model. METHODS AND ANALYSIS: IMPACT is a retrospective multicentre study which will aim to include 1500 patients with an incidental intracranial meningioma, powered to detect a 10% progression risk. Adult patients ≥16 years diagnosed with an incidental meningioma between 1 January 2009 and 31 December 2010 will be included. Clinical and radiological data will be collected longitudinally until the patient reaches one of the study endpoints: intervention (surgery, stereotactic radiosurgery or fractionated radiotherapy), mortality or last date of follow-up. Data will be uploaded to an online Research Electronic Data Capture database with no unique identifiers. External validity of IMPACT will be tested using established statistical methods. ETHICS AND DISSEMINATION: Local institutional approval at each participating centre will be required. Results of the study will be reported through peer-reviewed articles and conferences and disseminated to participating centres, patients and the public using social media