Ghost-arc geochemical anomaly at a spreading ridge caused by supersized flat subduction

The Southern Atlantic-Southwest Indian ridges (SASWIR) host mid-ocean ridge basalts with a residual subduction-related geochemical fingerprint (i.e., a ghost-arc signature) of unclear origin. Here, we show through an analysis of plate kinematic reconstructions and seismic tomography models that the SASWIR subduction-modified mantle source formed in the Jurassic close to the Georgia Islands slab (GI) and remained near-stationary in the mantle reference frame. In this analysis, the GI lies far inboard the Jurassic Patagonian-Antarctic Peninsula active margin. This was formerly attributed to a large-scale flat subduction event in the Late Triassic-Early Jurassic. We propose that during this flat slab stage, the subduction-modified mantle areas beneath the Mesozoic active margin and surrounding sutures zones may have been bulldozed inland by >2280 km. After the demise of the flat slab, this mantle anomaly remained near-stationary and was sampled by the Karoo mantle plume 183 Million years (Myr) ago and again since 55 Myr ago by the SASWIR. We refer to this process as asthenospheric anomaly telescoping. This study provides a hitherto unrecognized geodynamic effect of flat subduction, the viability of which we support through numerical modeling.G. M. G. and C. R. N. recognize the support given by CONICET and the funding given by the Universidad Nacional de la Patagonia San Juan Bosco (Grant number: CIUNPAT no. 1399). S. Z. and J. L. acknowledge the funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 777778. S.Z. acknowledges the funding of Project PID2020-113463RB-C32 funded by MCIN/AEI /10.13039/501100011033 and the funding of Generalitat de Catalunya via the 2021 SGR 01049.Peer ReviewedPostprint (published version

Cretaceous deformation of the southern Central Andes: synorogenic growth strata in the Neuquén Group (35° 300–37° S)

The Neuquén Group is an Upper Cretaceous continental sedimentary unit exhumed during the latest Miocene contractional phase occurred in the southern Central Andes, allowing a direct field observation and study of the depositional geometries. The identification of growth strata on these units surrounding the structures of the frontal parts of the Andes, sedimentological analyses and U–Pb dating of detrital components, allowed the definition of a synorogenic unit that coexisted with the uplift of the early Andean orogen since ca. 100 Ma, maximum age obtained in this work, compatible with previous assignments and constrained in the top by the deposition of the Malarg€ue Group, in the Maastrichtian (ca. 72 Ma). The definition of a wedge top area in this foreland basin system, where growth strata were described, permitted to identify a Late Cretaceous orogenic front and foredeep area, whose location and amplitude contrast with previous hypotheses. This wedge top area was mostly fed from the paleo-Andes with small populations coming from sources in the cratonic area that are interpreted as a recycling in Jurassic and Lower Cretaceous sections, which contrasts with other analyses performed at the foredeep zone that have mixed sources. In particular, Permian sources are interpreted as coming directly from the cores of the basement structures, where Neopaleozoic sections are exposed, next to the synorogenic sedimentation, implying a strong incision in Late Cretaceous times with an exhumation structural level similar to the present. The maximum recognised advance for this Late Cretaceous deformation in the study area is approximately 500 km east of the Pacific trench, which constitutes an anomaly compared with neighbour segments where Late Cretaceous deformations were found considerably retracted. The geodynamic context of the sedimentation of this unit is interpreted as produced under the westward fast moving of South America, colliding with two consecutive mid-ocean ridges during a period of important plate reorganisation. The subduction of young, anhydrous, buoyant lithosphere would have produced changes in the subduction geometry, reflected first by an arc waning/gap and subsequently by an arc migration that coexisted with synorogenic sedimentation. These magmatic and deformational processes would be the product of a shallow subduction regime, following previous proposals, which occurred in Late Cretaceous times, synchronous to the sedimentation of the Neuqu en Group.Facultad de Ciencias Naturales y Muse

Thermal Suppression of Strong Pinning

We study vortex pinning in layered type-II superconductors in the presence of uncorrelated disorder for decoupled layers. Introducing the new concept of variable-range thermal smoothing, we describe the interplay between strong pinning and thermal fluctuations. We discuss the appearance and analyze the evolution in temperature of two distinct non-linear features in the current-voltage characteristics. We show how the combination of layering and electromagnetic interactions leads to a sharp jump in the critical current for the onset of glassy response as a function of temperature.Comment: LaTeX 2.09, 4 pages, 2 figures, submitted to Phys. Rev. Let

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

<div><p>Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in <i>Cftr^F508del</i> homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the <i>F508del-CFTR</i> mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from <i>F508del</i> homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both <i>in vivo</i>, in mice, and <i>in vitro</i>, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 <i>F508del-CFTR</i> homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells <i>in vivo</i>, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of <i>TNF/TNF-alpha (tumor necrosis factor)</i> and <i>CXCL8</i> (<i>chemokine [C-X-C motif] ligand 8</i>) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the <i>F508del-CFTR</i> mutation.</p></div

Conversion gastrectomy for stage IV unresectable gastric cancer: a GIRCG retrospective cohort study

Background: The aim of this study is to report the experience with conversion surgery from six Gruppo Italiano Ricerca Cancro Gastrico (GIRCG) centers, focusing our analysis on factors affecting survival and the risk of recurrence. Methods: A retrospective, multicenter cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2017. Data were extracted from a GIRCG database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-five resected M1 patients were included in the analysis. Reasons for being deemed unresectable at diagnosis were peritoneal involvement (PCI &gt; 6) (n = 38, 84.4%), distant metastatic nodes (n = 3, 6.6%) and extensive liver involvement (n = 4, 8.8%). Median follow-up was 25&nbsp;months (IQR 9-50). Median overall survival from surgery was 15&nbsp;months and 1-, 3- and 5-year survivals were 57.2, 36.1 and 24%, respectively. Median progression-free survival was 12&nbsp;months with 1- and 3-year survival of 46.4 and 33.9%, respectively. At cox regression analysis the only independent prognostic factor for OS was the presence of more than one type of metastasis (HR 4.41, 95% CI 1.72\u201311.3, p = 0.002). A positive microscopic resection margin was the only risk factor for recurrence (HR 5.72, 95% CI 1.04\u201331.4, p = 0.045). Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. The main prognostic factor for these patients was the presence of more than one type of extra-gastric metastatic involvement

The neutrophil to lymphocyte ratio (NLR) and the presence of large nodal mass are independent predictors of early response: A subanalysis of the prospective phase II PET-2-adapted HD0607 trial

The neutrophil to lymphocyte ratio (NLR) and the lymphocyte to monocyte ratio (LMR) can reflect both the myeloid dysfunction and T-cell immune suppression and have prognostic significance

Structured and shared CT radiological report of gastric cancer: a consensus proposal by the Italian Research Group for Gastric Cancer (GIRCG) and the Italian Society of Medical and Interventional Radiology (SIRM)

Objectives Written radiological report remains the most important means of communication between radiologist and referring medical/surgical doctor, even though CT reports are frequently just descriptive, unclear, and unstructured. The Italian Society of Medical and Interventional Radiology (SIRM) and the Italian Research Group for Gastric Cancer (GIRCG) promoted a critical shared discussion between 10 skilled radiologists and 10 surgical oncologists, by means of multi-round consensus-building Delphi survey, to develop a structured reporting template for CT of GC patients. Methods Twenty-four items were organized according to the broad categories of a structured report as suggested by the European Society of Radiology (clinical referral, technique, findings, conclusion, and advice) and grouped into three "CT report sections" depending on the diagnostic phase of the radiological assessment for the oncologic patient (staging, restaging, and follow-up). Results In the final round, 23 out of 24 items obtained agreement ( >= 8) and consensus ( 0.05). Conclusions The structured report obtained, shared by surgical and medical oncologists and radiologists, allows an appropriate, clearer, and focused CT report essential to high-quality patient care in GC, avoiding the exclusion of key radiological information useful for multidisciplinary decision-making

Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis

<p>Abstract</p> <p>Purpose</p> <p>to investigate the factors affecting survival and toxicity in patients treated with stereotactic radiosurgery (SRS), with special attention to volumes of brain receiving a specific dose (V10 - V16 Gy) as predictors for brain radionecrosis.</p> <p>Patients and Methods</p> <p>Two hundred six consecutive patients with 310 cerebral metastases less than 3.5 cm were treated with SRS as primary treatment and followed prospectively at University of Rome La Sapienza Sant'Andrea Hospital. Overall survival, brain control, and local control were estimated using the Kaplan-Meier method calculated from the time of SRS. Univariate and multivariate analysis using a Cox proportional hazards regression model were performed to determine the predictive value of prognostic factors for treatment outcome and SRS-related complications.</p> <p>Results</p> <p>Median overall survival and brain control were 14.1 months and 10 months, respectively. The 1-year and 2-year survival rates were 58% and 24%, and respective brain control were 43% and 22%. Sixteen patients recurred locally after SRS, with 1-year and 2-year local control rates of 92% and 84%, respectively. On multivariate analysis, stable extracranial disease and KPS >70 were associated with the most significant survival benefit. Neurological complications were recorded in 27 (13%) patients. Severe neurological complications (RTOG Grade 3 and 4) occurred in 5.8% of patients. Brain radionecrosis occurred in 24% of treated lesions, being symptomatic in 10% and asymptomatic in 14%. On multivariate analysis, V10 through V16 Gy were independent risk factors for radionecrosis, with V10 Gy and V12 Gy being the most predictive (p = 0.0001). For V10 Gy >12.6 cm³and V12 Gy >10.9 cm³the risk of radionecrosis was 47%.</p> <p>Conclusions</p> <p>SRS alone represents a feasible option as initial treatment for patients with brain metastases, however a significant subset of patients may develop neurological complications. Lesions with V12 Gy >8.5 cm³carries a risk of radionecrosis >10% and should be considered for hypofractionated stereotactic radiotherapy especially when located in/near eloquent areas.</p

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2DBCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; by a Stand Up to Cancer Innovative Research Grant and St. Baldrick’s Foundation Scholar Award (to C.G.M.); by a St. Baldrick’s Consortium Award (S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex’s Lemonade Stand Foundation Young Investigator Awards (K.R.), by an Alex’s Lemonade Stand Foundation Award (M.L.) and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (C.L.W. and S.P.H.), U24 CA114737 (to Dr Gastier-Foster), NCI Contract HHSN261200800001E (to Dr Gastier-Foster), U10 CA180820 (ECOG-ACRIN Operations) and CA180827 (E.P.); U10 CA180861 (C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (C.L.W. and C.G.M.); and grants to the COG: U10 CA98543 (Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials