Miocene formations and NE-trending right-lateral strike–slip tectonism in Thrace, northwest Turkey: geodynamic implications

In the Thrace Peninsula, Neogene units were deposited in two areas, the Enez Basin in the south and the Thrace Basin in the north. In the southwesternmost part of the peninsula, upper lowerlower upper Miocene continental to shallow marine clastics of the Enez Formation formed under the influence of the Aegean extensional regime. During the last stage of the transpressional activity of the NW-trending right-lateral strikeslip BalkanThrace Fault, which had controlled the initial early middle Eocene deposition in the Thrace Basin, a mountainous region extending from Bulgaria eastwards to the northern Thrace Peninsula of Turkey developed. A river system carried erosional clasts of the metamorphic basement southwards into the limnic depositional areas of the Thrace Basin during middle Miocene time. Deposition of fluvial, lacustrine, and terrestrial strata of the Ergene Formation, which conformably and transitionally overlie the Enez Formation, began in the late middle Miocene in the southwest part and in the late Miocene in the north-northeast part of the basin. Activity along the NE-trending right-lateral strikeslip faults (the XanthiThrace Fault Zone) extending from northeast Greece northeastwards through the Thrace Peninsula of Turkey to the southern shelf of the western Black Sea Basin began during the middle Miocene in the northern Aegean, at the beginning of the late Miocene in the southwest part, and at the end of the late Miocene in the northeast part of the Thrace region. Although the Neogene deposits in the Thrace Basin were evaluated as the products of a northerly fault, our data indicate that the NW-trending northerly fault zone became effective only during the initial stage of the basin development. The later stage deposition in the basin was controlled by the NE-trending XanthiThrace Fault Zone, and the deposits of this basin progressively evolved north/northeastwards during the late Miocene. During the late early Miocenelate Miocene interval, extension within the Thrace region was part of the more regional Aegean extensional realm, but from latest Miocene time, it has been largely decoupled from the Aegean extensional realm to the south

Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency

Background Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. Methods Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (T-FH), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. Results LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cT(FH) cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cT(FH) frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway

Glass: Global lorlatinib for ALK(+) and ROS1(+) retrospective study: Real world data of 123 NSCLC patients

Lorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1( + ) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib.Methods: 123 patients were enrolled retrospectively (data cut-off 1/1/2019). Lorlatinib was administered through an early access program for patients with no other available therapy. Outcome and response were defined by each investigator upon RECIST 1.1 criteria.Results: 106 ALK(+) and 17 ROS1(+) patients recruited from 8 different countries. The ALK( + ) cohort included 50 % males, 73 % never-smokers and 68 % with brain metastases. Extracranial (EC) and intracranial (IC) response rates (RR) were 60 % and 62 %, with disease control rates (DCR) of 91 % and 88 % respectively. Mean duration of therapy (DoT) was 23.9 +/- 1.6 months and median overall survival (mOS) was 89.1 +/- 19.6 months. ROS1 cohort enrolled 53 % males, 65 % never-smokers and 65 % had brain metastases. EC and IC RR were 62 % and 67 % with DCR of 92 % and 78 % respectively. Median DoT was 18.1 +/- 2.5 months and mOS of 90.3 +/- 24.4 months. OS and DoT in both cohorts were not significantly correlated with line of therapy nor other parameters.The most common adverse events of any grade were peripheral edema (48 %), hyperlipidemia (47 %), weight gain (25 %) and fatigue (30 %). CNS adverse events such as cognitive effect of grade 1-2 were reported in 18 % of patients.Conclusion: Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 +/- 19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 +/- 24 months is unprecedented for ROS1( + ) NSCLC.Pfize

Glass: Global lorlatinib for ALK(+) and ROS1(+) retrospective study: Real world data of 123 NSCLC patients

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