SEA SURFACE TEMPERATURES RECONSTRUCTION OF THE LAST 16,000 YEARS IN THE EASTERN MEDITERRANEAN SEA

A detailed study has been performed on two eastern Mediterranean box cores (BC02 and BC06) and on a southern Adriatic piston core (AD91-17) on the alkenone unsaturation ratio, a molecular proxy for past sea surface temperatures. The aim was to identify climatic events of the last 16 Ky, with particular attention on the conditions during formation of sapropel S1. All three temperature curves lack evidence for cooling in the Younger Dryas stadial and warming in the Boelling/Alleroed interstadial events. Just prior to the sapropel S1 base, SST cooled and increased by about 5°C during the sapropel deposition interval. Within sapropel S1, SST show a marked warming followed by a clear cooling. In the topmost intervals of the cores SST are mostly constant, but a warming event is always observed. This warming phase may correspond to the Medieval climatic Optimum (in the AD91-17 core) and to the Roman Optimum (in the box cores)

The Great Space Weather Event during February 1872 Recorded in East Asia

The study of historical great geomagnetic storms is crucial for assessing the possible risks to the technological infrastructure of a modern society, caused by extreme space-weather events. The normal benchmark has been the great geomagnetic storm of September 1859, the so-called "Carrington Event". However, there are numerous records of another great geomagnetic storm in February 1872. This storm, about 12 years after the Carrington Event, resulted in comparable magnetic disturbances and auroral displays over large areas of the Earth. We have revisited this great geomagnetic storm in terms of the auroral and sunspot records in the historical documents from East Asia. In particular, we have surveyed the auroral records from East Asia and estimated the equatorward boundary of the auroral oval to be near 24.3 deg invariant latitude (ILAT), on the basis that the aurora was seen near the zenith at Shanghai (20 deg magnetic latitude, MLAT). These results confirm that this geomagnetic storm of February 1872 was as extreme as the Carrington Event, at least in terms of the equatorward motion of the auroral oval. Indeed, our results support the interpretation of the simultaneous auroral observations made at Bombay (10 deg MLAT). The East Asian auroral records have indicated extreme brightness, suggesting unusual precipitation of high-intensity, low-energy electrons during this geomagnetic storm. We have compared the duration of the East Asian auroral displays with magnetic observations in Bombay and found that the auroral displays occurred in the initial phase, main phase, and early recovery phase of the magnetic storm.Comment: 28 pages, 5 figures, accepted for publication in the Astrophysical Journal on 31 May 201

Non-Equilibrium Processes in the Solar Corona, Transition Region, Flares, and Solar Wind \textit{(Invited Review)}

We review the presence and signatures of the non-equilibrium processes, both non-Maxwellian distributions and non-equilibrium ionization, in the solar transition region, corona, solar wind, and flares. Basic properties of the non-Maxwellian distributions are described together with their influence on the heat flux as well as on the rates of individual collisional processes and the resulting optically thin synthetic spectra. Constraints on the presence of high-energy electrons from observations are reviewed, including positive detection of non-Maxwellian distributions in the solar corona, transition region, flares, and wind. Occurrence of non-equilibrium ionization is reviewed as well, especially in connection to hydrodynamic and generalized collisional-radiative modelling. Predicted spectroscopic signatures of non-equilibrium ionization depending on the assumed plasma conditions are summarized. Finally, we discuss the future remote-sensing instrumentation that can be used for detection of these non-equilibrium phenomena in various spectral ranges.Comment: Solar Physics, accepte

Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explaine

COL1-Related Disorders: Case Report and Review of Overlapping Syndromes

Collagen type I mutations are related to wide phenotypic expressions frequently causing an overlap of clinical manifestations, in particular between Osteogenesis Imperfecta (OI) and Ehlers-Danlos syndrome (EDS). Both disorders present inter- and intra-familial clinical variability and several clinical signs are present in both diseases. Recently, after the observation that some individuals first ascertained by a suspicion of EDS resulted then carriers of pathogenic variants of genes known to primarily cause OI, some authors proposed the term “COL1-related overlap disorder” to describe these cases. In this paper, we report clinical, molecular, and biochemical information about an individual with a diagnosis of EDS with severe joint hypermobility who carries a pathogenic heterozygous variant in COL1A2 gene, and a benign variant in COL1A1 gene. The pathogenic variant, commonly ascribed to OI, as well as the benign variant, has been inherited from the individual's mother, who presented only mild signs of OI and the diagnosis of OI was confirmed only after molecular testing. In addition, we reviewed the literature of similar cases of overlapping syndromes caused by COL1 gene mutations. The reported case and the literature review suggest that the COL1-related overlap disorders (OI, EDS and overlapping syndromes) represent a continuum of clinical phenotypes related to collagen type I mutations. The spectrum of COL1-related clinical manifestations, the pathophysiology and the underlying molecular mechanisms support the adoption of the updated proposed term “COL1-related overlap disorder” to describe the overlapping syndromes

Assessing spleen stiffness by point shear‐wave elastography: Is it feasible and reproducible in patients with chronic liver disease? Is it useful to predict portal hypertension?

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Multiple Acquired Mutations Captured by Liquid Biopsy in the EGFR Addicted Metastatic Colorectal Cancer.

Clinical Practice Points • Metastatic colorectal cancer is one of the most common causes of cancer death worldwide. • Primary and acquired resistance mechanisms to anti-EGFR treatment are a challenging topic with several clinical implications. • Primary resistance is defined by the presence of activating mutations in BRAF and RAS genes before treatment initiation, while acquired resistance refers to the selection of pre-existing mutant clones or de novo acquisition of mutations under the pressure of anti EGFR treatment. • Testing mutations in RAS and BRAF genes as predictive biomarkers is mandatory. • Liquid biopsy has acquired growing importance and showed to be reliable when compared to tissue NGS. • Liquid biopsy offers a full overview of the genetic landscape of the disease, overcoming spatial and temporal heterogeneity, when compared to tissue biopsy. • Liquid biopsy can be used to capture the changes in biology of cancer cells under the selective pressure of targeted agents over time. • Using complementary techniques allows to increase the diagnostic power and the biological significance of the results

T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker

Simple Summary Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia. Given important therapeutic implications, it is crucial to identify T-LBL arising in this particular context. LIM domain only 2 (LMO2) is known to be overexpressed in almost all sporadic T-LBL and not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations. We retrospectively evaluated the clinical, morphological, immunohistochemical and molecular features of 11 cases of T-LBL occurring in the setting of myeloid/lymphoid neoplasms with eosinophilia and investigated the immunohistochemical expression of LMO2 in this setting of T-LBL. Interestingly, 9/11 cases were LMO2 negative, with only 2 cases showing partial expression. In our study, we would suggest that LMO2 immunostaining, as part of the diagnostic panel for T-LBL, may represent a useful marker to identify T-LBL developing in the context of myeloid/lymphoid neoplasms with eosinophilia. Background: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic implications. LIM domain only 2 (LMO2) is overexpressed in most T-LBL, but not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations (iT-LBP). Methods and Results: We retrospectively evaluated 11 cases of T-LBL occurring in the context of M/LNs-Eo. Clinical, histological, immunohistochemical and molecular features were collected and LMO2 immunohistochemical staining was performed. The critical re-evaluation of these cases confirmed the diagnosis of T-LBL with morphological, immunohistochemical and molecular features consistent with T-LBL occurring in M/LNs-Eo. Interestingly, LMO2 immunohistochemical analysis was negative in 9/11 cases, whereas only 2 cases revealed a partial LMO2 expression with a moderate and low degree of intensity, respectively. Conclusions: LMO2 may represent a potentially useful marker to identify T-LBL developing in the context of M/LNs-Eo. In this setting, T-LBL shows LMO2 immunohistochemical profile overlapping with cortical thymocytes and iT-LBP, possibly reflecting different molecular patterns involved in the pathogenesis of T-LBL arising in the setting of M/LNs-Eo

The Geriatric G8 Score Is Associated with Survival Outcomes in Older Patients with Advanced Prostate Cancer in the ADHERE Prospective Study of the Meet-URO Network

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care