Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status

Oxygen binding to tyrosinase from streptomyces antibioticus studied by laser flash photolysis

Microbial Biotechnolog

safety and efficacy of trifluridine tipiracil ftd tpi in metastatic colorectal cancer mcrc patients according to previous treatment with regorafenib in the international phase iiib preconnect study

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Tyrosinase-catalyzed oxidation of fluorophenols

The activity of the type 3 copper enzyme tyrosinase toward 2-, 3-, and 4-fluorophenol was studied by kinetic methods and H-1 and F-19 NMR spectroscopy. Whereas 3- and 4-fluorophenol react with tyrosinase to give products that undergo a rapid polymerization process, 2-fluorophenol is not reactive and actually acts as a competitive inhibitor in the enzymatic oxidation of 3,4-dihydroxyphenylalanine (L-dopa). The tyrosinase-mediated polymerization of 3- and 4-fluorophenols has been studied in detail. It proceeds through a phenolic coupling pathway in which the common reactive fluoro-quinone, produced stereospecifically by tyrosinase, eliminates an inorganic fluorine ion. The enzymatic reaction studied as a function of substrate concentration shows a prominent lag that is completely depleted in the presence Of L-dopa. The kinetic parameters of the reactions can be correlated to the electronic and steric effects of the fluorine substituent position. Whereas the fluorine electron withdrawing effect appears to control the binding of the substrates (K-m for 3- and 4-fluorophenols and K-1 for 2-fluorophenol), the k(cat) parameters do not follow the expected trend, indicating that in the transition state some additional steric effect rules the reactivity.Macromolecular Biochemistr

HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment

An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host's immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3'UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3'UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3'UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3'UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3'UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38-0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26-0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19-5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16-6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3'UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G

Eddy‐driven sediment transport in the Argentine Basin: Is the height of the Zapiola Rise hydrodynamically controlled?

In this study, we address the question whether eddy‐driven transports in the Argentine Basin can be held responsible for enhanced sediment accumulation over the Zapiola Rise, hence accounting for the existence and growth of this sediment drift. To address this question, we perform a 6 year simulation with a strongly eddying ocean model. We release two passive tracers, with settling velocities that are consistent with silt and clay size particles. Our experiments show contrasting behavior between the silt fraction and the lighter clay. Due to its larger settling velocity, the silt fraction reaches a quasisteady state within a few years, with abyssal sedimentation rates that match net input. In contrast, clay settles only slowly, and its distribution is heavily stratified, being transported mainly along isopycnals. Yet, both size classes display a significant and persistent concentration minimum over the Zapiola Rise. We show that the Zapiola Anticyclone, a strong eddy‐driven vortex that circulates around the Zapiola Rise, is a barrier to sediment transport, and hence prevents significant accumulation of sediments on the Rise. We conclude that sediment transport by the turbulent circulation in the Argentine Basin alone cannot account for the preferred sediment accumulation over the Rise. We speculate that resuspension is a critical process in the formation and maintenance of the Zapiola Rise

STAT1-deficient mice spontaneously develop estrogen receptor alpha-positive luminal mammary carcinomas

Abstract Introduction Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors. Methods We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study. Results Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity. Conclusions Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities

lba20tribe2 a phase iii randomized strategy study by gono in the 1st and 2nd line treatment of unresectable metastatic colorectal cancer mcrc patients pts

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Pregnancy-associated serum N-glycome changes studied by high-throughput MALDI-TOF-MS

Pregnancy requires partial suppression of the immune system to ensure maternal-foetal tolerance. Protein glycosylation, and especially terminal sialic acid linkages, are of prime importance in regulating the pro- and anti-inflammatory immune responses. However, little is known about pregnancy-associated changes of the serum N-glycome and sialic acid linkages. Using a combination of recently developed methods, i.e. derivatisation that allows the distinction between α2,3- and α2,6-linked sialic acids by high-throughput MALDI-TOF-MS and software-assisted data processing, we analysed the serum N-glycome of a cohort of 29 healthy women at 6 time points during and after pregnancy. A total of 77 N-glycans were followed over time, confirming in part previous findings while also revealing novel associations (e.g. an increase of FA2BG1S1(6), FA2G1S1(6) and A2BG2S2(6) with delivery). From the individual glycans we calculated 42 derived traits. With these, an increase during pregnancy and decrease after delivery was observed for both α2,3- and α2,6-linked sialylation. Additionally, a difference in the recovery speed after delivery was observed for α2,3- and α2,6-linked sialylation of triantennary glycans. In conclusion, our new high-throughput workflow allowed the identification of novel plasma glycosylation changes with pregnancy

Airborne observations of Arctic air mass transformations during the HALO-(AC)3 campaign

The HALO-(AC)3 campaign was conducted in March and April 2022 to investigate warm air intrusions into the Arctic and marine cold air outbreaks. In coordinated flights over the Arctic, the High Altitude and Long Range Research Aircraft (HALO), equipped with a remote sensing payload and dropsondes, investigated these air mass transformations together with the research aircraft Polar 5 and Polar 6. In this report, we give an overview about the research flights and preliminary results from projects, which are carried out by employees of the Leipzig Institute for Meteorology (LIM).Die HALO-(AC)3 Kampagne wurde im März und April 2022 durchgeführt, umWarmlufteinbrüche in die Arktis und marine Kaltluftausbrüche zu untersuchen. Das 'High Altitude and Long Range Research Aircraft' (HALO), ausgestattet mit Instrumenten zur Fernerkundung und Standardmeteorologiesonden, untersuchte zusammen mit den Forschungsflugzeugen Polar 5 und Polar 6, in koordinierten Flügen über der Arktis, diese Veränderungen der Luftmassen. In diesem Bericht wird eine Übersicht über die durchgeführten Forschungsflüge gegeben und Forschungsprojekte werden vorgestellt, welche von Mitarbeitern des Leipziger Instituts für Meteorologie (LIM) durchgeführt werden