Entry of ZSWIM4 to the nucleus is crucial for its inhibition of KIT and BMAL1 in gastrointestinal stromal tumors.

BACKGROUND: Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs). RESULTS: We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KITV558A/WT mice and KITV558A/WT/ZSWIM4-/- mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KITV558A/WT mice. CONCLUSIONS: Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.

Clinical and radiological outcomes of selective fusion for rotatory olisthesis in degenerative lumbar scoliosis: a retrospective cohort study.

STUDY DESIGN: Retrospective cohort study. PURPOSE: To investigate the long-term clinical and radiological outcomes of selective fusion for rotatory olisthesis (RO) in degenerative lumbar scoliosis (DLS). OVERVIEW OF LITERATURE: DLS is often associated with RO, and selective fusion of RO is a common surgical treatment option. However, the clinical and radiological outcomes remain controversial. METHODS: A cohort of 54 consecutive patients with DLS and RO was included in the study. All the included patients underwent selective RO fusion and at least 2 years of follow-up. They were divided into two groups: group 1 with a curve <30° and group 2 with a curve ≥30°. The clinical outcomes were evaluated by the Oswestry Disability Index (ODI) and Numerical Rating Scale. The radiological assessment included RO location, offset and subluxated-disc orientation, Cobb angle, and coronal as well as sagittal alignments. RESULTS: The offset value was greater in group 2 than in group 1 (13.4±4.7 mm vs. 9.3±3.5 mm, p<0.001). The subluxated disc was mainly oriented to the concave side in group 2 (15/21) but to the convex side in group 1 (20/33) (p =0.022). Group 2 had a higher rate of postoperative adjacent RO than group 1 (14/21 vs. 1/33, p<0.001). The ODI was comparable between both groups preoperatively but higher at the final follow-up in group 2 (34.9±9.5) than in group 1 (24.4±6.2). In the multiple logistic regression analysis, the thoracolumbar/lumbar curve was identified as the risk factor for postoperative adjacent RO (odds ratio, 1.400; p=0.007). The receiver operating characteristic analysis verified it with an area under the curve of 0.960 (p<0.001). CONCLUSIONS: The clinical and radiological outcomes were maintained well in group 1 but not in group 2. Selective RO fusion in DLS with a lumbar curve <30° is a rational option. However, it should be avoided in those with a lumbar curve >30° because of a higher complication rate and a worse clinical outcome at the final follow-up.

Eco-consciousness to eco-consumption: unraveling the drivers of sustainable consumption behavior under the mediated-moderated Model.

The impact of climate change has malformed the world's ecosystem, thus making humans call for environmental protection. Climate change, the biggest trauma of the twenty-first century, has made humans switch towards natural consumption. In this regard, the growing phenomenon of industrialization has spurred consumers to invest more in ecological products. Consuming eco-friendly products has several benefits; however, countries are still unable to satisfy the consumer's concern for the environment. The current study presents literature on environmental concerns, psychological well-being, willingness to pay for pro-environmental products, pro-environmental self-identity, and pro-environmental consumer behavior, which are required to ensure the consumer's organic behavior. The research used a questionnaire-driven methodology to gather data from 379 participants. Data analysis was conducted using statistical software packages, specifically SPSS (Version: 4.1.0.0). The suitability of the measurement model was evaluated through structural equation modeling (SEM), which was performed utilizing the SmartPLS. According to the research findings, there is a positive relationship between variables in the study, and individuals with greater levels of psychological well-being are more likely to engage in behaviors that promote sustainable consumption. In order to foster more sustainable consumption patterns in society, policymakers, marketers, and educators may find these findings to be valuable insights. As a result of its empirical exploration of these relationships, the study contributes to the growing body of literature on environmental psychology and sustainable marketing, emphasizing the important role psychological factors play in promoting a greener environment.

RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.

The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.

Bimetallic MnZn-MOF-74 with enhanced percentage of MnIII: Efficiently catalytic activity for direct oxidative carboxylation of olefins to cyclic carbonates under mild and solvent-free condition.

Multi-functional MOF catalyst with oxidative- and acid- centers showed potential in olefins oxidative carboxylation to cyclic carbonates directly. In this work, a series of bimetallic MnZn-MOF-74 with different molar ratios of Mn and Zn were synthesized successfully through a one-pot facile method. Thoroughly characterization indicated that the existence of Zn regulated the valance state distribution of Mn in the obtained MnZn-MOF-74. Mn99.3Zn0.7-MOF-74 with the highest ratio of MnIII (61.3 %) performed the most efficient activity for olefin direct tandem oxidative carboxylation reaction using aqueous tert-butyl hydroperoxide oxidant under solvent-free condition of 90 °C, 1.0 MPa CO2 and 4 h. Mn99.3Zn0.7-MOF-74 also showed satisfactory versatility and recyclability. Based on the experiments, a feasible mechanism was presented. Thanks to the high ratio of active MnIII as main oxidative center, the coordination unsaturated bimetal Mn and Zn as Lewis-acid sites, O2- of metal - O as Lewis-base sites and combined effect with Bu4NBr cocatalyst, Mn99.3Zn0.7-MOF-74 presented efficient performance for the direct synthesis of cyclic carbonates from olefins. The metal Zn in MOF can regulate the valance state distribution of Mn and result in efficient catalytic property, presenting a potential avenue for direct oxidative carboxylation reaction of olefins to cyclic carbonates synthesis.

Green transition in the hospitality industry: The influence of market forces and customer dynamics on sustainable performance in the digital era.

In recent years, the ongoing environmental challenges have caused hotel firms to experience stress from stakeholders (i.e., customers and competitors). These stringent ecological changes have compelled hospitality firms to go green. This study investigates the influence of customer and competitive pressures on green innovation and sustainability in the hospitality industry. Utilizing a sample of 309 employees from multiple hospitality companies, the study rigorously tests a series of hypotheses using Smart PLS and Partial Least Squares Structural Equation Modeling (PLS-SEM). The findings supported all the hypotheses, indicating that customer and competitive pressures significantly foster green product and process innovations, enhance sustainable firm performance, and encourage green CSR initiatives in the Chinese hospitality sector. Furthermore, green product innovation, green process innovation, and green CSR were found to be critical mediators in enhancing firm performance under the influence of these pressures. These results have substantial implications for theory and practice, highlighting the importance of external pressures in promoting sustainable practices in the hospitality industry.

Spinopelvic morphology impacts on postoperative proximal junctional kyphosis in congenital scoliosis with thoracolumbar hemivertebrae.

PURPOSE: It aims to investigate the lumbar and pelvic morphology in congenital scoliosis with thoracolumbar hemivertebrae and its impact on proximal junctional kyphosis (PJK) incidence after hemivertebra resection and short fusion. METHODS: 23 congenital scoliosis patients with thoracolumbar hemivertebra aged between 10 and 18 years were enrolled in the retrospective study. Spinopelvic sagittal parameters were analyzed on whole-spine standing lateral radiographs preoperatively, one-week postoperatively and at the final follow-up. Pearson correlations were calculated for local kyphosis (LK), lumbar and pelvic morphology parameters. Binary logistic regression and receiver operating characteristics (ROC) curve analysis were performed to identify the risk factors for PJK. RESULTS: Thoracolumbar hemivertebra caused LK of 29.2° ± 17.3°, an increased lumbar lordosis (LL) (-64.7° ± 16.3°), lower LL apex (52.2% at L5), and small pelvic incidence (PI) (36.8° ± 6.6°). LK was correlated with lumbar morphology parameters, including LL (r = - 0.837), upper arc of LL (LLUA) (r = - 0.879), thoracolumbar kyphosis (TLK) (r = 0.933), thoracic kyphosis (TK) (r = 0.762) and TK apex (TKA) (r = - 0.749). Surgical treatment improved the lumbar morphology, but not pelvic morphology. At the final follow-up, LL had returned to its preoperative value (p = 0.158). PJK occurred in 30.4% of cases as a compensatory mechanism. Preoperatively, significant differences of parameters between non-PJK and PJK groups were observed in LK and TLK. Binary logistic regression identified three independent risk factors for PJK: preoperative LLA (OR = 0.005, 95%CI = 0.000-0.287, p = 0.011), preoperative TLK (OR = 1.134, 95%CI = 1.001-1.286, p = 0.048), and preoperative lumbar lordosis morphology type (OR = 5.507, 95%CI = 1.202-25.227, p = 0.028). However, residual LK after surgery was not correlated with PJK incidence. ROC curve analysis verified that preoperative TLK > 22.59° was associated with increased PJK incidence after surgery. CONCLUSIONS: Lumbar morphology changes as a compensatory mechanism beneath the thoracolumbar hemivertebra. However, a stable pelvis tends to allow the LL to return to its preoperative value. PJK occurred as a cranial compensatory mechanism for increasing LL and corrected TLK. A larger TLK (> 22.59°) was an independent risk factor for PJK incidence in patients with type 2 and 3A lumbar lordosis morphology.

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

Erector Spinae Atrophy Correlates with Global Sagittal Imbalance and Postoperative Proximal Junctional Kyphosis Incidence in Lumbar Degenerative Kyphosis.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to investigate the relationship between lumbar erector muscle atrophy and global sagittal imbalance in lumbar degenerative kyphosis (LDK) and with postoperative proximal junctional kyphosis. OVERVIEW OF LITERATURE: Lumbar erector muscle atrophy has been studied in LDK. However, its role in the compensatory mechanism is still under intense discussion, and the role of erector spinae (ES) muscle is always overlooked. METHODS: This study enrolled 51 patients with LDK out of 382 patients with adult degenerative spinal deformity. Baseline information was reviewed including demographic data and complications. Sagittal spinopelvic alignments and global imbalance parameters were assessed on full-length X-ray images of the spine. Muscularity and the fatty infiltration area of the ES and multifidus (MF) were measured at the L4/5 level on preoperative magnetic resonance image to evaluate the lumbar erector muscle atrophy. Stratification by sagittal vertical axis (SVA) was performed: group 1 with SVA <100 mm and group 2 with SVA >100 mm, and these groups were compared. Spearman correlation and multivariable logistic regression analyses were performed to analyze and define risk factors of postoperative proximal junctional kyphosis (PJK). RESULTS: Group 2 had lower ES and MF muscularity than group 1. ES muscularity correlated with SVA (r=-0.510, p<0.003), lumbar lordosis (r=-0.415, p<0.018), and postoperative PJK (r=-0.508, p<0.022). MF muscularity did not correlate with the above parameters. Multivariable logistic regression analysis verified ES muscularity (odds ratio [OR], 0.001; p<0.039) and SVA (OR, 1.034; p<0.048) as the risk factors for postoperative PJK. CONCLUSIONS: ES atrophy, besides the MF, is an important predictor in distinguishing decompensated LDK from well-compensated ones. It plays an important role in compensatory mechanism, not only correlates with global sagittal imbalance but also ties to PJK after deformity corrective surgery.

ZSWIM4 regulates embryonic patterning and BMP signaling by promoting nuclear Smad1 degradation.

The dorsoventral gradient of BMP signaling plays an essential role in embryonic patterning. Zinc Finger SWIM-Type Containing 4 (zswim4) is expressed in the Spemann-Mangold organizer at the onset of Xenopus gastrulation and is then enriched in the developing neuroectoderm at the mid-gastrula stages. Knockdown or knockout of zswim4 causes ventralization. Overexpression of zswim4 decreases, whereas knockdown of zswim4 increases the expression levels of ventrolateral mesoderm marker genes. Mechanistically, ZSWIM4 attenuates the BMP signal by reducing the protein stability of SMAD1 in the nucleus. Stable isotope labeling by amino acids in cell culture (SILAC) identifies Elongin B (ELOB) and Elongin C (ELOC) as the interaction partners of ZSWIM4. Accordingly, ZSWIM4 forms a complex with the Cul2-RING ubiquitin ligase and ELOB and ELOC, promoting the ubiquitination and degradation of SMAD1 in the nucleus. Our study identifies a novel mechanism that restricts BMP signaling in the nucleus.

Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of gastrointestinal stromal tumor (GIST).

BACKGROUND: Mutations in the receptor tyrosine kinase KIT are the main cause of gastrointestinal stromal tumor (GIST), and the KIT mutants mediated PI3 kinase activation plays a key role in the tumorigenesis of GIST. In this study, we aimed to block PI3 kinase activation by cell-permeable peptide and investigate its possible application in the treatment of GIST. METHODS AND RESULTS: We designed cell-permeable peptides based on the binding domain of PI3 kinase subunit p85 to KIT or PI3 kinase subunit p110, respectively, in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of PI3 kinases mediated by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of PI3 kinases, leading to reduced cell survival and cell proliferation mediated by KIT mutants in vitro. Treatment of mice carrying germline KIT/V558A mutation, which can develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorigenesis of GIST. The peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of GIST. CONCLUSIONS: Our results showed that cell-permeable PI3 kinase competitive peptide can inhibit KIT-mediated PI3 kinase activation and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of GIST and even other tumors with over-activation of PI3 kinases.

PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Corrigendum: Two small-molecule inhibitors of Toxoplasma gondii proliferation in vitro.

[This corrects the article DOI: 10.3389/fcimb.2023.1145824.].

The pathogenesis of post-stroke osteoporosis and the role oxidative stress plays in its development.

Cardiovascular disease and osteoporotic fractures (OF) are the main diseases affecting the health of middle-aged and elderly people. With the gradual increase of population aging in China and even the world, the incidence of the two and the prevalence of high-risk groups are also showing a continuous upward trend. The relationship between the two, especially the impact of cardiovascular disease on the risk and prognosis of OF, has attracted more and more attention. Therefore, it is of great significance to fully understand the pathogenesis of cardiovascular and cerebrovascular diseases and the resulting osteoporosis and to provide targeted interventions to prevent the occurrence of diseases and fractures. This article reviews the relationship between one of the Cardiovascular disease-stroke and related therapeutic drugs and the risk of OF, and the role of oxidative stress in its pathophysiological mechanism by reviewing relevant domestic and foreign literature in recent years, in order to gain a more comprehensive understanding of the association between stroke and OF, and then provide a basis and reference for screening high-risk groups of fractures and reducing the burden on the health system caused by the disease.

Relationship between Fusion Mass Shift and Postoperative Distal Adding-on in Lenke 1 Adolescent Idiopathic Scoliosis after Selective Thoracic Fusion.

STUDY DESIGN: This is a retrospective cohort study. PURPOSE: This study aims to investigate the risk factors for postoperative distal adding-on in Lenke 1 adolescent idiopathic scoliosis (AIS) and validate the relationship between fusion mass shift (FMS) and postoperative distal adding-on. OVERVIEW OF LITERATURE: Postoperative distal curve adding-on is one of the complications in AIS. FMS has been proposed to prevent postoperative distal adding-on, which requires further validation from different institutions. METHODS: This study included 60 patients with Lenke 1 AIS who underwent selective thoracic fusion surgery. Coronal spinal alignment parameters were analyzed preoperatively, postoperatively, and at the final follow-up. The postoperative FMS was divided into two groups: the balanced group (FMS ≤20 mm) and the unbalanced group (FMS >20 mm). An independent t-test was used to compare quantitative data between groups, and a chi-square test was used for qualitative data. Furthermore, binary logistic regression and receiver operating characteristics curve analyses were used to identify the risk factors for postoperative distal adding-on in AIS. RESULTS: At 2-year follow-up, the unbalanced group was more likely to have adding-on (17 of 24 patients) than the balanced group (six of 36 patients; p<0.001). Twenty-three patients with distal adding-on had significantly greater preoperative and postoperative lower instrumented vertebrae (LIV) rotation, FMS, and FMS angle (FMSA) than those without postoperative distal adding-on. Binary logistic regression analysis selected three independent risk factors for adding-on incidence after surgery: FMS (odds ratio [OR], 1.115; 95% confidence interval [CI], 1.049-1.185; p<0.001), FMSA (OR, 1.590; 95% CI, 1.225-2.064; p<0.001), and postoperative LIV rotation (OR, 6.581; 95% CI, 2.280-19.000; p<0.001). CONCLUSIONS: Achieving a balanced fusion mass intraoperatively is important to avoid postoperative distal adding-on, with FMS of <20 mm and FMS angle of <4.5°. Furthermore, correcting LIV rotation helps to decrease the incidence of postoperative distal addingon.

Predicting thoracic kyphosis morphology and the thoracolumbar inflection point determined by individual lumbar lordosis in asymptomatic adults.

PURPOSE: The aims of this study were to explore the correlations between thoracic kyphosis (TK) and lumbar lordosis (LL) parameters and to build corresponding linear regressions to predict TK morphology and the thoracolumbar inflection point (IP) determined by individual LL parameters in asymptomatic adults. METHODS: A total of 280 adult healthy volunteers were recruited, and full-spine X-rays were performed for each subject in a standing posture. The following sagittal parameters were measured: cumulative TK, LL, proximal LL (PLL), the apices of TK (TKA) and LL (LLA), the IP and the distance from the plumb line of the thoracic apex (TAPL) and the lumbar apex (LAPL) to the gravity line. The correlations between TK and LL parameters were analyzed, and the corresponding linear regressions were conducted. RESULTS: Extensive variations existed in TK alignment, including angular and morphological parameters. In addition, there were statistical correlations of all cumulative TK angles with LL (r values from - 0.173 to - 0.708) and PLL (r values from - 0.206 to - 0.803), TKA and IP with LLA (rs = 0.359 and 0.582, respectively) and TAPL with LAPL (rs = 0.335). The common predictive formulas employed in ASD surgery could include T10-L1 = - 3.6-0.2*LL (R2 = 0.201), T4-L1 = 3.4-0.5*LL (R2 = 0.457), TKA = - 10.3 + 1.1*LLA (R2 = 0.180) and IP = - 12.7 + 1.6*LLA (R2 = 0.330). CONCLUSION: There were intimate associations between TK and LL parameters in asymptomatic adults. Moreover, predictive models for thoracic alignment, particularly cumulative TK, based on LL parameters were proposed, which could better delineate anatomical relationships, guide thoracic construction during adult spinal deformity surgery and may help preventing proximal junctional failure.

Effects of Methyl Substitution and Leaving Group on E2/SN2 Competition for Reactions of F- with RY (R = CH3, C2H5, iC3H7, tC4H9; Y = Cl, I).

The competition between base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) is of significant importance in organic chemistry and is influenced by many factors. The electronic structure calculations for the gas-phase reactions of F- + RY (R = CH3, C2H5, iC3H7, tC4H9, and Y = Cl, I) are executed at the MP2 level with aug-cc-pVDZ or ECP/d basis set to investigate the α-methyl substitution effect. The variation in barrier height, reaction enthalpy, and competition of SN2/E2 as a function of methyl-substitution and leaving group ability has been emphasized. And the nature of these rules has been explored. As the degree of methyl substitution on α-carbon increases, the E2 channel becomes more competitive and dominant with R varying from C2H5, iC3H7, to tC4H9. Energy decomposition analysis offers new insights into the competition between E2 and SN2 processes, which suggests that the drop in interaction energy with an increasing degree of substitution cannot compensate for the rapid growth of preparation energy, leading to a rapid increase in the SN2 energy barrier. By altering the leaving group from Cl to I, the barriers of both SN2 and E2 monotonically decrease, and, with the increased number of substituents, they reduce more dramatically, which is attributed to the looser transition state structures with the stronger leaving group ability. Interestingly, ∆E0‡ exhibits a positive linear correlation with reaction enthalpy (∆H) and halogen electronegativity. With the added number of substituents, the differences in ∆E0‡ and ∆H between Y = Cl and I likewise exhibit good linearity.

Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib.

Background: Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. Methods: The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot. Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

The Nexus Between Ethical Leadership and Employees' Perception of Workplace Safety During COVID-19 Under Mediation and Moderation Model.

Background: Workplace safety is a crucial aspect of employee well-being and organizational success, with ethical leadership playing a key role in shaping employees' perceptions of safety. Today, the underlying mechanisms through which ethical leadership influences workplace safety perception remain underexplored, especially in the Pakistan healthcare industry. Based on the social cognitive theory, this study aims to investigate the relationship between ethical leadership and workplace safety perception and examine the mediating role of media quality, communication climate, and supervisory communication and the moderating role of moral attentiveness. Methods: An empirical survey method was used to conduct the quantitative study, with respondents representing nursing staff from hospitals in Pakistan. Data was collected using an online questionnaire during COVID-19, and Smart PLS was used to analyze the data. Results: The study demonstrated that ethical leadership positively and significantly affects workplace safety perception. Media quality, communication climate, and supervisory communication mediate between ethical leadership and workplace safety perception. Moral attentiveness moderates the relationship between ethical leadership and workplace safety perception. Conclusion: Ethical leadership is an essential tool that improves media quality, communication climate, supervisory communication, and moral attentiveness. The article presents a novel approach to examining the relationship between ethical leadership and workers' safety perceptions under the influence of mediating and moderating variables. By better understanding these dynamics, the study contributes to developing organizational strategies to improve workplace safety and overall employee well-being. In addition, it is a pioneering study exploring ethical leadership's role in influencing workers' perceptions of safety. Overall, the study is a great initiative that fosters the ethical concepts of individuals, thus achieving health protection and safety.