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Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6–19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. Amgen.

The Ribosome-associated Quality Control (RQC) pathway co-translationally marks incomplete polypeptides from stalled translation with two signals that trigger their proteasome-mediated degradation. The E3 ligase Ltn1 adds ubiquitin and Rqc2 directs the large ribosomal subunit to append carboxy-terminal alanine and threonine residues (CAT tails). When excessive amounts of incomplete polypeptides evade Ltn1, CAT-tailed proteins accumulate and can self-associate into aggregates. CAT tail aggregation has been hypothesized to either protect cells by sequestering potentially toxic incomplete polypeptides or harm cells by disrupting protein homeostasis. To distinguish between these possibilities, we modulated CAT tail aggregation in Saccharomyces cerevisiae with genetic and chemical tools to analyze CAT tails in aggregated and un-aggregated states. We found that enhancing CAT tail aggregation induces proteotoxic stress and antagonizes degradation of CAT-tailed proteins, while inhibiting aggregation reverses these effects. Our findings suggest that CAT tail aggregation harms RQC-compromised cells and that preventing aggregation can mitigate this toxicity.

Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT. We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints. We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 109/L with rhTPO vs 122 x 109/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 109/L with rhTPO vs 28 x 109/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis (n = 23 studies) and bleeding (n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents. Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

This article explores how transnationalism can be understood as an interdiscursive process. By making connections with chronotopes of past places along a transmigrant's trajectory, interdiscursivity allows for the emergence of complex indexical meaning associated with different speakers and different ways of speaking, imbuing the transmigrant's mobility with specific social significance. This article demonstrates this point through an analysis of how South Korean mid-level managers of multinational corporations in Singapore imagined their positioning in the global workplace. By tracing the ways the managers employed metapragmatic discourse associated with multiple chronotopes to make sense of their reasonably successful but limited careers, it offers an account of how interdiscursivity shaped their understanding of their own positionality as Koreans working beyond the time-space of Korea. (Interdiscursivity, transnationalism, chronotope, Korea, English, intercultural communication)*

Streptococcus equi subsp. zooepidemicus (SEZ) is a zoonotic pathogen capable of causing meningitis in humans. The mechanisms that enable pathogens to traverse the blood-brain barrier (BBB) are incompletely understood. Here, we investigated the role of a newly identified Fic domain-containing protein, BifA, in SEZ virulence. BifA was required for SEZ to cross the BBB and to cause meningitis in mice. BifA also enhanced SEZ translocation across human Brain Microvascular Endothelial Cell (hBMEC) monolayers. Purified BifA or its Fic domain-containing C-terminus alone were able to enter into hBMECs, leading to disruption of monolayer barrier integrity. A SILAC-based proteomic screen revealed that BifA binds moesin. BifA's Fic domain was required for its binding to this regulator of host cell cytoskeletal processes. BifA treatment of hBMECs led to moesin phosphorylation and downstream RhoA activation. Inhibition of moesin activation or moesin depletion in hBMEC monolayers abrogated BifA-mediated increases in barrier permeability and SEZ's capacity to translocate across monolayers. Thus, BifA activation of moesin appears to constitute a key mechanism by which SEZ disrupts endothelial monolayer integrity to penetrate the BBB.

This article analyzes \"success stories\" of English language learning in the Korean conservative press as tales of neoliberal personhood, locating the stories within South Korea's neoliberal transformation and its concomitant \"English frenzy.\" In these texts, the semiotic process of leveling — the simultaneous work of erasure and highlighting — naturalizes the successful learner's competence in English by grounding that competence in the subjective, human qualities of the speaker. By obscuring class-based constraints on access to English that determine the structure of the Korean linguistic market, this process ultimately rationalizes and justifies the neoliberal logic of human capital development.

Background MicroRNAs (miRNAs) are small RNAs (sRNAs) approximately 21 nucleotides in length that negatively control gene expression by cleaving or inhibiting the translation of target gene transcripts. Within this context, miRNAs and siRNAs are coming to the forefront as molecular mediators of gene regulation in plant responses to annual temperature cycling and cold stress. For this reason, we chose to identify and characterize the conserved and non-conserved miRNA component of peach ( Prunus persica (L.) Batsch) focusing our efforts on both the recently released whole genome sequence of peach and sRNA transcriptome sequences from two tissues representing non-dormant leaves and dormant leaf buds. Conserved and non-conserved miRNAs, and their targets were identified. These sRNA resources were used to identify cold-responsive miRNAs whose gene targets co-localize with previously described QTLs for chilling requirement (CR). Results Analysis of 21 million peach sRNA reads allowed us to identify 157 and 230 conserved and non-conserved miRNA sequences. Among the non-conserved miRNAs, we identified 205 that seem to be specific to peach. Comparative genome analysis between peach and Arabidopsis showed that conserved miRNA families, with the exception of miR5021, are similar in size. Sixteen of these conserved miRNA families are deeply rooted in land plant phylogeny as they are present in mosses and/or lycophytes. Within the other conserved miRNA families, five families (miR1446, miR473, miR479, miR3629, and miR3627) were reported only in tree species ( Populus trichocarpa , Citrus trifolia , and Prunus persica ). Expression analysis identified several up-regulated or down-regulated miRNAs in winter buds versus young leaves. A search of the peach proteome allowed the prediction of target genes for most of the conserved miRNAs and a large fraction of non-conserved miRNAs. A fraction of predicted targets in peach have not been previously reported in other species. Several conserved and non-conserved miRNAs and miRNA-regulated genes co-localize with Quantitative Trait Loci (QTLs) for chilling requirement (CR-QTL) and bloom date (BD-QTL). Conclusions In this work, we identified a large set of conserved and non-conserved miRNAs and describe their evolutionary footprint in angiosperm lineages. Several of these miRNAs were induced in winter buds and co-localized with QTLs for chilling requirement and bloom date thus making their gene targets potential candidates for mediating plant responses to cold stress. Several peach homologs of genes participating in the regulation of vernalization in Arabidopsis were identified as differentially expressed miRNAs targets, potentially linking these gene activities to cold responses in peach dormant buds. The non-conserved miRNAs may regulate cellular, physiological or developmental processes specific to peach and/or other tree species.

In South Korea, English is a language of utmost importance, sought with an unprecedented zeal as an indispensable commodity in education, business, popular culture, and national policy. This book investigates how the status of English as a hegemonic language in South Korea is constructed through the mediation of language ideologies in local discourse. Adopting the framework of language ideology and its current developments, it is argued that English in Korean society is a subject of deep-rooted ambiguities, with multiple and sometimes conflicting ideologies coexisting within a tension-ridden discursive space. The complex ways in which these ideologies are reproduced, contested, and negotiated through specific metalinguistic practices across diverse sites ultimately contribute to a local realization of the global hegemony of English as an international language. Through its insightful analysis of metalinguistic discourse in language policy debates, cross-linguistic humor, television shows, and face-to-face interaction, The Local Construction of a Global Language makes an original contribution to the study of language and globalization, proposing an innovative analytic approach that bridges the gap between the investigation of large-scale global forces and the study of micro-level discourse practices.

To retrospectively determine the sensitivity of preoperative CT in the detection of small (≤ 10 mm) colorectal liver metastasis (CRLM) nodules in patients undergoing liver resection. The institutional review board approved the study and waived informed consent. We included 461 pathologically confirmed CRLM nodules in 211 patients (including 71 women; mean age, 66.4 years) who underwent 229 liver resections following abdominal CT. Prior to 163 resections, gadoxetic acid-enhanced liver MR imaging was also performed. Nodules were matched between pathology reports and prospective CT reports following a predefined algorithm. Per-nodule sensitivity of CT was calculated by nodule-size category. Generalized estimating equations were used to adjust for within-case correlation. Fourteen nodule sizes were missing in the pathology report. Nodules of 1-5 mm and 6-10 mm accounted for 8.1% (n = 36) and 23.5% (n = 105) of the remaining 447 nodules, and the number of nodules gradually decreased as nodule size increased beyond 10 mm. The overall sensitivity of CT was 81.2% (95% confidence interval, 77.1%, 85.2%; 365/461). The sensitivity was 8% (0%, 17%; 3/36), 55% (45%, 65%; 59/105), 91%, 95%, and 100% for nodules of 1-5 mm, 6-10 mm, 11-15 mm, 16-20 mm, and >20 mm, respectively. The nodule-size distribution was similar between resections undergoing gadoxetic acid-enhanced MR imaging and those not undergoing the MR imaging. CT has limited sensitivity for nodules of ≤ 10 mm and particularly of ≤ 5 mm.

Intravenous ferric carboxymaltose (IV-FCM) can effectively correct perioperative anemia in patients undergoing major surgeries. However, its efficacy and side effects in patients undergoing free flap-based breast reconstruction are yet to be investigated. At our institution, from year 2020, patients with breast cancer undergoing abdominal free flap-based breast reconstruction were injected 500 mg of IV-FCM immediately post-operation. Propensity-matched 82 IV-FCM injected (study group) and 164 historical control group patients were retrospectively analyzed for transfusion rates, changes in hematological parameters, and flap or donor-site related complications. The major and minor complication rates related to the operation site were similar between the two groups. There was no significant difference in the transfusion rate between the two groups (control 29.9% vs. study 32.9%, p = 0.71). However, the total amount of transfusion required was significantly higher in the historical control group (control—53.2% 1 pack, 42.6% 2 packs, 4.3% 3 packs of RBC vs. Study—66.7% 1 pack, 33.3% 2 packs, p = 0.02) than in the study group. Additionally, the historical control group showed a significantly higher drop in red blood cell count, hemoglobin, and hematocrit levels from postoperative days 1–2 and 2–3 compared to the study group. Immediate postoperative use of IV-FCM in free flap-based breast reconstruction was well tolerated by patients and reduced overall transfusion volume.