ABSTRACT
Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for â¼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
Subject(s)
Protein Kinases/metabolism , Proteolysis , Proteome/metabolism , Adult , Cell Line , Databases, Protein , Female , Humans , Male , Middle Aged , Proteasome Endopeptidase Complex/metabolism , Protein Kinases/genetics , Proteomics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ubiquitin-Protein Ligases/metabolism , Young AdultABSTRACT
Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 µM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Cell Cycle Proteins , Aurora Kinase A , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , DNA Replication , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.
Subject(s)
Indazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Indazoles/pharmacology , Drug Resistance, Neoplasm , Imatinib Mesylate/pharmacology , Imatinib Mesylate/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Benzamides/pharmacology , Cell Line, Tumor , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Mutation , Cell Proliferation , ApoptosisABSTRACT
BRAF mutants are categorized into three classes according to dependency on RAS signaling and RAF dimerization-dependency. Class I BRAF V600 mutants (RAS-independent monomer) are sensitive to vemurafenib. In contrast, both class II mutants (RAS-independent dimer) and class III mutants (RAS-dependent heterodimer) are insensitive to vemurafenib. It is not likely that BRAF inhibitors capable of inhibiting all classes of BRAF mutants are currently available. Herein, we report GNF-7 and its novel derivative, SIJ1227 as the first BRAF inhibitors capable of inhibiting all classes of BRAF mutants. Compared with vemurafenib and PLX8394, both GNF-7 and SIJ1227 possess much more strong anti-proliferative activities on melanoma (A375 and C8161) and lung cancer cells (H1755 and H1666) harboring BRAF V600E (class I mutant), BRAF G464E/G469A (class II mutant) and BRAF G466V (class III mutant), respectively. Also, both GNF-7 and SIJ1227 are capable of inhibiting more strongly colony formation than vemurafenib and PLX8394 in 3D soft agar assay using C8161 melanoma cells. In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.
Subject(s)
Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Proliferation/genetics , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor/methods , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Molecular Docking Simulation , Mutation , Proto-Oncogene Proteins B-raf/chemistry , Pyrimidinones/pharmacology , Vemurafenib/pharmacologyABSTRACT
Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.
Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Anaplastic Lymphoma Kinase/metabolism , Apoptosis/drug effects , Carbon-13 Magnetic Resonance Spectroscopy , Cell Line, Transformed , Cell Proliferation/drug effects , Chromatography, Liquid , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Proton Magnetic Resonance Spectroscopy , Pyrazoles/chemistry , Pyridines/chemistry , Signal Transduction/drug effects , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Objective This study assessed gender-specific associations between low muscle mass (LMM) and albuminuria. Methods Data from the Korea National Health and Nutrition Examination Survey 2011 were employed. The study consisted of 1,087 subjects (≥50 years old). Skeletal muscle index (SMI) was defined as the weight-adjusted appendicular skeletal muscle mass. Mild LMM and severe LMM were defined as SMI that were 1-2 and >2 standard deviations below the sex-specific mean appendicular skeletal muscle mass of young adults, respectively. Increased albuminuria was defined as albumin-to-creatinine ratio ≥30mg/g Results Men with mild and severe LMM were significantly more likely to have increased albuminuria (15.2% and 45.45%, respectively) than men with normal SMI (9.86%, P<0.0001), but not women. Severe LMM associated independently with increased albuminuria in men (OR=7.661, 95% CI=2.72-21.579) but not women. Severe LMM was an independent predictor of increased albuminuria in hypertensive males (OR=11.449, 95% CI=3.037-43.156), non-diabetic males (OR=8.782, 95% CI=3.046-25.322), and males without metabolic syndrome (MetS) (OR=8.183, 95% CI=1.539-43.156). This was not observed in males without hypertension, males with diabetes or MetS, and all female subgroups. Conclusion Severe LMM associated with increased albuminuria in men, especially those with hypertension and without diabetes or MetS.
Subject(s)
Body Weight/physiology , Diabetes Mellitus/physiopathology , Hypertension/physiopathology , Muscle, Skeletal/physiopathology , Obesity/physiopathology , Aged , Aged, 80 and over , Albuminuria/blood , Albuminuria/physiopathology , Creatinine/blood , Diabetes Mellitus/blood , Female , Humans , Hypertension/blood , Male , Metabolic Syndrome/blood , Metabolic Syndrome/physiopathology , Middle Aged , Obesity/blood , Risk Factors , Serum Albumin/metabolism , Sex CharacteristicsABSTRACT
PURPOSE: The immunochemical fecal occult blood test (iFOBT) is a useful method to screen for lower gastrointestinal (GI) bleeding-related lesions. However, few studies have investigated the diagnostic utility of iFOBT in chronic kidney disease (CKD). METHODS: We included 691 patients with nondialysis-dependent CKD stages 2-5 or those receiving dialysis. Bleeding-related lower GI lesions were identified by colonoscopy, and the diagnostic utility of iFOBT was evaluated. RESULTS: Bleeding-related lower GI lesions were found in 9.2% of 491 patients with CKD stage 2, 17.8% of 107 patients with CKD stage 3/4, and 25.8% of 93 patients with CKD stage 5/dialysis (p < 0.001). Compared with CKD stage 2, CKD stage 5/dialysis was independently associated with a 2.80-fold risk for bleeding-related lesions (p = 0.019). The iFOBT was positive in 92 (13.3%) patients and the area under the receiver operating curve (AUC) for a bleeding-related lesion was 0.64 (p < 0.001). The sensitivity of iFOBT increased as the CKD stage worsened (20.0 vs 52.6 vs 58.3%; p = 0.002). However, the specificity to detect bleeding-related lesions decreased with the severity of CKD stage (94.6 vs. 78.4 vs. 76.8%; p < 0.001). The AUC of iFOBT to detect adenoma or carcinoma was 0.54 (p = 0.046), and a similar pattern of sensitivity and specificity was observed between different CKD stages. CONCLUSIONS: The prevalence of bleeding-related lower GI lesions and the sensitivity of iFOBT to detect these GI lesions increased in advanced CKD. However, iFOBT should be used cautiously in these patients because its specificity decreased.
Subject(s)
Immunohistochemistry/methods , Lower Gastrointestinal Tract/pathology , Occult Blood , Renal Insufficiency, Chronic/complications , Aged , Colonoscopy , Demography , Female , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/diagnosis , Gastrointestinal Hemorrhage/epidemiology , Humans , Male , Middle Aged , Prevalence , ROC CurveABSTRACT
We examined financial capability and asset ownership among low-income older Asian immigrants with special attention given to later-age immigrants who came to the United States when they were 55 years old or older. Survey data collected from supported employment program participants (N = 150) were used. The analyses demonstrated a low level of financial knowledge and asset ownership in the sample. The findings also indicated that later-age immigrants' financial-management skills, knowledge of social programs, and asset ownership were significantly lower than those of young-age immigrants. These findings call for active interventions to enhance economic security among low-income older Asian immigrants.
Subject(s)
Asian People/statistics & numerical data , Emigration and Immigration , Ownership/economics , Poverty/economics , Aged , Female , Humans , Male , Middle Aged , Population Dynamics/statistics & numerical data , Surveys and Questionnaires , United StatesABSTRACT
The authors would like to make a correction to the previous article [...].
ABSTRACT
This study pragmatically investigates an artificial intelligence (AI) speaker (AIS)'s verbal communicative performance based on real AI-human conversation data. Specifically, this study explores Grice's conversation theory, which enables the categorization of an AIS's mistaken utterances as violations of specific conversational maxims. Twenty native Korean-speaking participants recorded at least 50 conversations with Kakao Mini AISs, provided by Daum Kakao, Inc., in Korea. Each conversation, either for information sharing or as daily dialogue, was required to contain at least two turn-taking instances. A total of 1,026 recorded dialogues were decomposed into adjacency pairs based on turn-taking. The dialogues were arranged into 3,365 adjacency pairs, and each pair was then classified as a conversational success or failure based on whether the AIS answered the user's utterance appropriately. Language users' evaluations of the AIS's mistaken expressions were also quantified via an additional acceptability rating test with 1,024 adjacency pairs. The overall results indicate that Grice's "maxim of relation" is most frequently flouted by AISs and is considered to be the least natural to language users. These findings suggest that to improve AISs' natural communication capacity, more detailed AI algorithms that generate utterances relevant to either the partner's preceding utterance or a broader conversational context should be created. Although the verbal communicative capacities of the AIS we test are substantially overtaken by those of recent large language models, such as generative pretrained transformer, the pragmatic evaluation described in the current study will remain useful for more precise linguistic quantification of current/future language AI's communicative performance/competence.
Subject(s)
Artificial Intelligence , Communication , Language , Humans , Information Dissemination , East Asian People , Psychological TheoryABSTRACT
To investigate whether language rules the visual features that can be discriminated (a radical assumption of linguistic relativity), we examined crosslinguistic differences between native Korean and German speakers during liminal perception of a target disk that was difficult to perceive because its visibility suffered from masking by a ring that followed and enclosed the target disk (metacontrast-masking). Target-mask fit varied, with half of the masks tightly and the other half loosely encircling the targets. In Korean, such tight versus loose spatial relations are semantically distinguished and thus highly practiced, whereas in German, they are collapsed within a single semantic category, thus are not distinguished by language. We expected higher sensitivity and greater attention to varying spatial target-mask distances in Korean than in German speakers. This was confirmed in Experiment 1, where Korean speakers consistently outperformed German speakers in discriminating liminal metacontrast-masked stimuli. To ensure that this effect was not attributable to generic differences in attention capture or by language-independent differences between participant groups, we investigated stimulus-driven attention capture by color singletons and conducted a control experiment using object-substitution masking, where tightness of fit was not manipulated. We found no differences between Korean and German speakers regarding stimulus-driven attention capture or perceptual sensitivity. This was confirmed in Experiment 3, where we manipulated types of masking within participants. In addition, we validated the tightness-of-fit manipulation in a language-related task (Experiment 4). Overall, our results are consistent with linguistic relativity, namely its assumed generalized language influences in nonlinguistic perceptual tasks. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Subject(s)
Language , Linguistics , Humans , Semantics , Perception , Perceptual MaskingABSTRACT
Necroptosis executed by RIPK3-mediated phosphorylation of MLKL is a programmed necrotic cell death and implicated with various diseases such as sterile inflammation. We designed and synthesized pyrido[3,4-d]pyrimidine derivatives as novel necroptosis inhibitors capable of suppressing the phosphorylation of MLKL. Our SAR studies reveal that 20 possesses comparable inhibitory activity against RIPK3-mediated pMLKL in HT-29 cells relative to GSK872 (2), a representative selective RIPK3 inhibitor. Based on biochemical kinase assay results, 20 is comparable to GSK872 (2) with regard to activity against RIPK3 and less potent against RIPK1 than GSK872, indicating selectivity of 20 towards RIPK3 over RIPK1 is higher than that of GSK872. In HT-29 cells, 20 inhibits necroptosis via MLKL oligomerization impediment. Moreover, 20 suppresses migration and invasion of AsPC-1 cells by necroptosis induced- CXCL5 secretion downregulation. Significantly, 20 could relieve the TNFα-induced systemic inflammatory response syndrome in vivo. Taken together, this study would provide a useful insight into the design of novel necroptosis inhibitors possessing RIPK3-mediated pMLKL inhibitory activity.
Subject(s)
Necroptosis , Protein Kinases , Humans , Apoptosis , Necroptosis/drug effects , Necrosis , Protein Kinases/metabolism , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/metabolismABSTRACT
This study investigated a subject-first strategy in prediction mechanism in visually situated sentence processing in Korean, using event-related potentials (ERPs). According to the subject-first strategy, parsers tend to generate sentences conforming to canonical sentence word order (i.e., SOV in Korean), subject-first sentence, mapping conceptually more prominent referent such as agent of the event on the subject position of the sentence. Therefore, in the predictive mechanism of language comprehension, the subject is pre-activated and anticipated for the first NP of the sentence at the initial phase of bottom-up language processing. This study tested this subject-first strategy in Korean by examining brain responses to object-initial sentences (OV) compared with subject-initial sentences (SV) under the context of clear thematic role relations set by a visual image. The results of an ERP experiment with 30 native Korean speakers identified neural effects for object-initial sentences compared with subject-initial sentences at the NP and Verb, reflecting a conflict between the pre-activated representation in the parser's mind and the encountered bottom-up input. An N400 effect was elicited at the NP, as early as at the noun, not at the following object case marker. Late frontal positivity (LFP) was also found in the sentence-final verb, proving the processing difficulty of non-canonical object-initial sentences compared with canonical subject-initial sentences. These results indicate that Korean native speakers build linguistic representation conforming to a canonical sentence in SOV language in the predictive mechanism supporting subject-first strategy but revise the predicted event structure rapidly upon newly encountering input.
Subject(s)
Comprehension , Evoked Potentials , Humans , Male , Female , Evoked Potentials/physiology , Comprehension/physiology , Electroencephalography , Language , Auditory PerceptionABSTRACT
This study investigated whether the degree of cybersickness varies depending on different virtual reality experience modes (playing vs. watching) and whether specific eye movement parameters reflect changes in cybersickness. Simulator Sickness Questionnaire results from 20 participants (10 playing and 10 watching) showed that cybersickness was much more severe in the watching mode, particularly during the second of the three total trials. Moreover, cybersickness' changing pattern was reflected in the center gaze ratio and scan-path length. These findings imply the importance of physiological measurements for a deeper understanding of cybersickness in theoretical and practical respects.
Subject(s)
Motion Sickness , Virtual Reality , Eye Movements , Humans , Surveys and QuestionnairesABSTRACT
Hepatocellular carcinoma (HCC) is disease with a high mortality rate and limited treatment options. Alterations of fibroblast growth factor receptor 4 (FGFR4) has been regarded as an oncogenic driver for HCC and a promising target for HCC therapeutics. Herein, we report that GNF-7, a multi-targeted kinase inhibitor, and its derivatives including SIJ1263 (IC50 < 1 nM against FGFR4) are highly potent FGFR4 inhibitors and are capable of strongly suppressing proliferation of HCC cells and Ba/F3 cells transformed with wtFGFR4 or mtFGFR4. Compared with known FGFR4 inhibitors, both GNF-7 and SIJ1263 possess much higher (up to 100-fold) anti-proliferative activities via FGFR signaling blockade and apoptosis on HCC cells. Especially, SIJ1263 is 80-fold more potent (GI50 = 24 nM) on TEL-FGFR4 V550E Ba/F3 cells than BLU9931, which suggests that SIJ1263 would be effective for overriding drug resistance. In addition, both substances strongly suppress migration/invasion and colony formation of HCC cells. It is worth noting that SIJ1263 is superior to GNF-7 with regards to the fact that activities of SIJ1263 are higher than those of GNF-7 in all assays performed in this study. Collectively, this study provides insight into designing highly potent FGFR4 inhibitors capable of potentially overcoming drug-resistance for the treatment of HCC patients.
Subject(s)
Antineoplastic Agents/pharmacology , Pyrimidinones/pharmacology , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Signal Transduction/drug effects , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Models, Molecular , Molecular Conformation , Molecular Structure , Pyrimidinones/chemistry , Receptor, Fibroblast Growth Factor, Type 4/genetics , Structure-Activity RelationshipABSTRACT
Although FGFR inhibitors hold promise in treating various cancers, resistance to the FGFR inhibitors caused by acquired secondary mutations has emerged. To discover novel FGFR inhibitors capable of inhibiting FGFR mutations, including gatekeeper mutations, we designed and synthesized several new pyridinyltriazine derivatives. A structure-activity relationship (SAR) study led to the identification of 17a as a highly potent panFGFR inhibitor against wild-type and mutant FGFRs. Notably, 17a is superior to infigratinib in terms of kinase-inhibitory and cellular activities, especially against V555M-FGFR3. Molecular dynamics simulations provide a clear understanding of why pyridinyltraizine derivative 17a possesses activity against V555M-FGFR3. Moreover, 17a significantly suppresses proliferation of cancer cells harboring FGFR mutations via FGFR signaling blockade, cell cycle arrest, and apoptosis. Furthermore, 17a and 17b exhibited remarkable efficacies in TEL-V555M-FGFR3 Ba/F3 xenograft mouse model and 17a is more efficacious than infigratinib. This study provides new insight into the design of novel FGFR inhibitors that are active against FGFR mutants.
Subject(s)
Antineoplastic Agents , Protein Kinase Inhibitors , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Line, Tumor , Cell Proliferation , Drug Resistance , Humans , Mice , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal TransductionABSTRACT
c-KIT is a promising therapeutic target against gastrointestinal stromal tumor (GIST). In order to identify novel c-KIT inhibitors capable of overcoming imatinib resistance, we synthesized 31 novel thiazolo[5,4-b]pyridine derivatives and performed SAR studies. We observed that, among these substances, 6r is capable of inhibiting significantly c-KIT and suppressing substantially proliferation of GIST-T1 cancer cells. It is of note that 6r is potent against a c-KIT V560G/D816V double mutant resistant to imatinib. Compared with sunitinib, 6r possesses higher differential cytotoxicity on c-KIT D816V Ba/F3 cells relative to parental Ba/F3 cells. In addition, kinase panel profiling reveals that 6r has reasonable kinase selectivity. It was found that 6r remarkably attenuates proliferation of cancer cells via blockade of c-KIT downstream signaling, and induction of apoptosis and cell cycle arrest. Furthermore, 6r notably suppresses migration and invasion, as well as anchorage-independent growth of GIST-T1 cells. This study provides useful SAR information for the design of novel c-KIT inhibitors overcoming imatinib-resistance.
ABSTRACT
Immigrants' access to federally-funded Medicaid became limited after welfare reform imposed restrictive noncitizen eligibility rules. This study used a representative sample from the Current Population Survey (N = 105,873) and state-level data to examine the effects of these policy changes on elderly immigrants. Triple difference-in-differences analyses show that federal restriction of eligibility had a significantly negative association with elderly immigrants' Medicaid coverage, and generous state eligibility had significantly positive relationships with Medicaid and any health insurance coverage. Findings indicate the important role of eligibility on elderly immigrants' health insurance coverage. Results call for social workers' actions to expand elderly immigrants' Medicaid eligibility.
Subject(s)
Emigrants and Immigrants/legislation & jurisprudence , Geriatrics/legislation & jurisprudence , Insurance Coverage/legislation & jurisprudence , Medical Assistance/legislation & jurisprudence , Social Welfare/legislation & jurisprudence , Age Factors , Aged , Aged, 80 and over , Aging , Data Collection , Eligibility Determination/legislation & jurisprudence , Federal Government , Female , Government Programs/legislation & jurisprudence , Health Policy , Humans , Insurance, Health/legislation & jurisprudence , Logistic Models , Male , Medicaid/legislation & jurisprudence , Medicare/legislation & jurisprudence , New York , State Government , United StatesABSTRACT
RAS mutants are involved in approximately 30% of all human cancers and have been regarded as undruggable targets owing to relatively smooth protein surface and obscure binding pockets. In our previous study, we have demonstrated that GNF-7, a multi-targeted kinase inhibitor, possesses potent anti-proliferative activity against Ba/F3 cells transformed with NRAS-G12D. Based on our further analysis using Ba/F3 cells transformed with mtRAS, we discovered a series of pyrimido[4,5-d]pyrimidin-2-one analogues as mtRAS-signaling pathway blockers. In addition, our efforts expanded the assessment to cancer cells with mtRAS, which revealed that these substances are also capable of strongly suppressing the proliferation of various cancer cells harboring KRAS-G12D (AsPC-1), KRAS-G12V (SW480, DU-145), KRAS-G12C (H358), KRAS-G13D (MDA-MB-231), KRAS-Q61L (HT-29), and NRAS-Q61L (OCI-AML3). We herein report novel and potent mtRAS-signaling pathway blockers, SIJ1795 and SIJ1772, possessing 2 to 10-fold increased anti-proliferative activities compared to those of GNF-7 on cancer cells harboring mtRAS as well as on Ba/F3 cells transformed with mtRAS. Both SIJ1795 and SIJ1772 attenuate phosphorylation of RAS downstream molecules (AKT and MEK) and induce apoptosis and G0/G1 cell cycle arrest on cancer cells with mtRAS. Moreover, both substances substantially suppress the migration, invasion, and colony formation of cancer cells harboring mtRAS. Taken together, this study led us to identification of SIJ1795 and SIJ1772 capable of strongly inhibiting mtRAS-signaling pathway on cancer cells harboring mtRAS.
ABSTRACT
In Korean, it is allowed for an adjective to modify a distant noun that appears after an intervening relative clause instead of an adjacent noun. The current study investigated the time course of syntactic and semantic integration between an adjective (A) and an adjacent noun (N1) and/or a distant noun (N2) during on-line reading comprehension of Korean sentences. Semantic congruence between adjectives and nouns were manipulated, such that A was congruent with both N1 and N2, either with N1 or N2, or with none of N1/N2. The reading times and ERPs to critical words revealed that under A-N1 semantic incongruence, not the processing load of N1, but those of the relative clause verb and N2 which is semantically incongruent with A increased. These results imply that the semantic incongruence suppressed the A-N1 integration until the relative clause verb occurred, and the processor immediately attempted the A-N2 integration for a way out from the ultimate processing breakdown even before the occurrence of the main verb.