Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and ...are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic ...acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site ...alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.
Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
This investigation delves into the pervasive yet insufficiently examined phenomenon of "cyberloafing", characterized by employees engaging in non-work-related internet activities during office hours. ...Despite its frequent occurrence in contemporary work environments, the fundamental mechanisms underpinning cyberloafing remain largely uncharted. This study uses the conservation of resources theory and the cognitive-affective personality system framework to demystify the relationship between role stress and cyberloafing. We developed a dual-path model to assess the mediating roles of perceived insider status and emotional exhaustion. Employing SPSS and Smart PLS for data analysis, our research sampled 210 corporate employees. The findings reveal that role stress predicts perceived insider status and emotional exhaustion significantly. Notably, while perceived insider status negatively correlates with cyberloafing, emotional exhaustion shows a positive correlation. These factors mediate the relationship between role stress and cyberloafing, underscoring a multifaceted dynamic. Our results provide new theoretical insights into the mechanisms of employee counterproductive behavior, specifically in the context of cyberloafing, and broaden our understanding of its determinants. This study illuminates theoretical nuances and offers practical implications for managerial strategies and future scholarly inquiries into organizational behavior.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Open innovation communities (OICs) have been expanding the scope of enterprises' innovation activities, and their effective functioning hinges on the ongoing knowledge contributions from users. ...However, the research on the impact of contractual governance mechanisms on users' knowledge-contribution behaviors has yet to be further explored. In this study, we provide a comprehensive definition of implicit contracts in OICs, clarify their dimensions, investigate their impact on users' knowledge contribution, and explore how users' network positions moderate these effects. Subsequently, we employ a questionnaire survey combined with web crawling to collect user data and empirically test the theoretical hypotheses. The results demonstrate that both user-user implicit contracts (i.e., user reciprocity, user trust, and user recognition) and user-community implicit contracts (i.e., community incentives, community trust, and community support) significantly and positively affect user knowledge contribution. Furthermore, users' structural holes exert a significant positive moderating effect on these relationships. Notably, the moderating effect of network centrality is only significant in the influence of user-community implicit contracts, and not significant in the relationship between user-user implicit contracts and user knowledge contribution. The insights derived from this study offer valuable practical guidance for effectively operating and managing OICs.
Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (
) near the exon 14 splice ...sites are recurrent in lung adenocarcinoma and cause exon skipping (
Δ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping.
Δ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor-dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward
Δ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an
system for the study of
Δ14 in an immunocompetent host.
.
We propose a bi-layer 5-tip edge coupler in a multilayer silicon nitride-on-silicon (SiN-on-Si) waveguide platform. The coupler is used for the integration between a monolithic 1550 nm laser and a ...single-mode SiN waveguide. The simulated coupling efficiency is 92.8%. The vertical 1-dB-loss misalignment tolerance is as large as 0.5 μm. Broad 1-dB-drop bandwidth (1338 nm to 1700 nm) and small footprint (total length: 38.2 μm) are achieved simultaneously. A broadband bi-layer SiN-Si adiabatic transition cascaded to the edge coupler is designed to couple the laser power into a single-mode Si waveguide at an efficiency of 90.6%. Low-computation-cost electromagnetic numerical simulation and optimization strategies are applied to improve the reverse design of the complex couplers.
Mycobacterium
is a kind of disease-causing bacteria and results in leprosy in human. Gamma delta (γδ) T cell is a T-cell subset that is presented in both human dermis and epidermis. These cells ...bridge innate and adaptive immune responses and play critical roles in regulating anti-microbial defense, wound healing, and skin inflammation. Here, we investigated skin resident γδ T cells in patients with leprosy. Our data showed that γδ T cells significantly accumulated in skin lesions of leprosy patients with tuberculoid (TT) form. IL-23 can predominantly stimulate dermal γδ T cells to produce interleukin 17 (IL-17), a cytokine which may lead to disease protection. These γδ T cells expressed a specific set of surface molecules, and majority of these cells were Vδ1
. Also, IL-23 can stimulate the expansion of dermal γδ T cells expansion. Moreover, our results revealed that the transcription factor RORγt was responsible for IL-17A expression in leprosy lesion. Therefore, these data indicated that IL-23-responsive dermal γδ T cells were the major resource of IL-17A production in the skin and could be a potential target in the treatment of leprosy.
Cement stabilized soil (CSS) yields wide application as a routine cementitious material due to cost-effectiveness. However, the mechanical strength of CSS impedes development. This research assesses ...the feasible combined enhancement of unconfined compressive strength (UCS) and flexural strength (FS) of construction and demolition (C&D) waste, polypropylene fiber, and sodium sulfate. Moreover, machine learning (ML) techniques including Back Propagation Neural Network (BPNN) and Random Forest (FR) were applied to estimate UCS and FS based on the comprehensive dataset. The laboratory tests were conducted at 7-, 14-, and 28-day curing age, indicating the positive effect of cement, C&D waste, and sodium sulfate. The improvement caused by polypropylene fiber on FS was also evaluated from the 81 experimental results. In addition, the beetle antennae search (BAS) approach and 10-fold cross-validation were employed to automatically tune the hyperparameters, avoiding tedious effort. The consequent correlation coefficients (R) ranged from 0.9295 to 0.9717 for BPNN, and 0.9262 to 0.9877 for RF, respectively, indicating the accuracy and reliability of the prediction. K-Nearest Neighbor (KNN), logistic regression (LR), and multiple linear regression (MLR) were conducted to validate the BPNN and RF algorithms. Furthermore, box and Taylor diagrams proved the BAS-BPNN and BAS-RF as the best-performed model for UCS and FS prediction, respectively. The optimal mixture design was proposed as 30% cement, 20% C&D waste, 4% fiber, and 0.8% sodium sulfate based on the importance score for each variable.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely ...develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance.
190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance.
We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs.
Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance.
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