RESUMO
KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in â¼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.
Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , HumanosRESUMO
KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.
Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Animais , Camundongos , Peso Corporal , Ativação Enzimática , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Nucleotídeos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Especificidade por SubstratoRESUMO
Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Acetonitrilas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular , Estudos de Coortes , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma1,2. KRAS(G12C) inhibitors3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation4-6, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.
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Mutação , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Adaptação Biológica , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Cellular proliferation depends on the accurate and timely replication of the genome. Several genetic diseases are caused by mutations in key DNA replication genes; however, it remains unclear whether these genes influence the normal program of DNA replication timing. Similarly, the factors that regulate DNA replication dynamics are poorly understood. To systematically identify trans-acting modulators of replication timing, we profiled replication in 184 cell lines from three cell types, encompassing 60 different gene knockouts or genetic diseases. Through a rigorous approach that considers the background variability of replication timing, we concluded that most samples displayed normal replication timing. However, mutations in two genes showed consistently abnormal replication timing. The first gene was RIF1, a known modulator of replication timing. The second was MCM10, a highly conserved member of the pre-replication complex. Cells from a single patient carrying MCM10 mutations demonstrated replication timing variability comprising 46% of the genome and at different locations than RIF1 knockouts. Replication timing alterations in the mutated MCM10 cells were predominantly comprised of replication delays and initiation site gains and losses. Taken together, this study demonstrates the remarkable robustness of the human replication timing program and reveals MCM10 as a novel candidate modulator of DNA replication timing.
Assuntos
Período de Replicação do DNA , Proteínas de Manutenção de Minicromossomo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Replicação do DNA/genética , Período de Replicação do DNA/genética , Humanos , Proteínas de Manutenção de Minicromossomo/genética , Origem de ReplicaçãoRESUMO
The Mec1/Tel1 kinases (human ATR/ATM) play numerous roles in the DNA replication stress response. Despite the multi-functionality of these kinases, studies of their in vivo action have mostly relied on a few well-established substrates. Here we employed a combined genetic-phosphoproteomic approach to monitor Mec1/Tel1 signaling in a systematic, unbiased, and quantitative manner. Unexpectedly, we find that Mec1 is highly active during normal DNA replication, at levels comparable or higher than Mec1's activation state induced by replication stress. This "replication-correlated" mode of Mec1 action requires the 9-1-1 clamp and the Dna2 lagging-strand factor and is distinguishable from Mec1's action in activating the downstream kinase Rad53. We propose that Mec1/ATR performs key functions during ongoing DNA synthesis that are distinct from their canonical checkpoint role during replication stress.
Assuntos
Replicação do DNA , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteômica/métodos , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/análise , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
INTRODUCTION: Local applications of tranexamic acid (TXA) have been effective in treating various hemorrhagic conditions. In patients with gross hematuria, the main treatment in the emergency department (ED) is continuous bladder irrigation (CBI). However, CBI has no pharmacological effects except blood clot removal from dilution. The aim of this study was to evaluate the impact of the intravesical TXA injection before CBI. METHODS: This study was a before-and-after, retrospective, and single-center study. The target population was hematuria patients who received CBI via a 3-way Foley catheter. As the intervention procedure, 1000 mg of TXA was injected through the Foley catheter and after 15 min, the Foley catheter was declamped and CBI started. Since the intervention started in March 2022, the patients from March 2022 to August 2022 were assigned to the after group and the patients from March 2021 to August 2021 were assigned to the before group. The primary outcomes were the length of stay in the ED and duration of Foley catheter placement. The secondary outcomes were the admissions and the revisits for CBI within 48 h after discharge. RESULTS: The numbers of patients in the before group and after group were 73 and 86, respectively. The median length of stay in the ED was shorter in the intervention group than in the group not treated with TXA (274 min vs. 411 mins, P < 0.001). The median duration of Foley catheter placement was also shorter in the intervention group than not treated with TXA (145 min vs. 308 mins, P < 0.001). The revisits after ED discharge were lower in the after group than in the before group (2.3% vs. 12.3%, P = 0.031). There was a trend for lower admissions in the TXA treatment group than before group (29.1% vs. 45.2%, P = 0.052). CONCLUSION: After the TXA intervention, reduction in the length of stay in the ED, the duration of Foley catheter placement, and the revisits after ED discharge was observed.
Assuntos
Antifibrinolíticos , Ácido Tranexâmico , Humanos , Ácido Tranexâmico/uso terapêutico , Antifibrinolíticos/uso terapêutico , Hematúria/tratamento farmacológico , Administração Intravesical , Estudos Retrospectivos , Resultado do Tratamento , Serviço Hospitalar de EmergênciaRESUMO
The objective of this study was to prepare an angiotensin I-converting enzyme (ACE)-inhibitory peptide from the hydrothermal vent mussel, Gigantidas vrijenhoeki. The G. vrijenhoeki protein was hydrolyzed by various hydrolytic enzymes. The peptic hydrolysate exhibited the highest ACE-inhibitory activity and was fractionated into four molecular weight ranges by ultrafiltration. The <1 kDa fraction exhibited the highest ACE inhibitory activity and was found to have 11 peptide sequences. Among the analyzed peptides, KLLWNGKM exhibited stronger ACE inhibitory activity and an IC50 value of 0.007 µM. To investigate the ACE-inhibitory activity of the analyzed peptides, a molecular docking study was performed. KLLWNGKM exhibited the highest binding energy (-1317.01 kcal/mol), which was mainly attributed to the formation of hydrogen bonds with the ACE active pockets, zinc-binding motif, and zinc ion. These results indicate that G. vrijenhoeki-derived peptides can serve as nutritional and pharmacological candidates for controlling blood pressure.
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Mytilidae , Peptidil Dipeptidase A , Animais , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , ZincoRESUMO
BACKGROUND: Rapid revascularization is the key to better patient outcomes in ST-elevation myocardial infarction (STEMI). Direct activation of cardiac catheterization laboratory (CCL) using artificial intelligence (AI) interpretation of initial electrocardiography (ECG) might help reduce door-to-balloon (D2B) time. To prove that this approach is feasible and beneficial, we assessed the non-inferiority of such a process over conventional evaluation and estimated its clinical benefits, including a reduction in D2B time, medical cost, and 1-year mortality. METHODS: This is a single-center retrospective study of emergency department (ED) patients suspected of having STEMI from January 2021 to June 2021. Quantitative ECG (QCG™), a comprehensive cardiovascular evaluation system, was used for screening. The non-inferiority of the AI-driven CCL activation over joint clinical evaluation by emergency physicians and cardiologists was tested using a 5% non-inferiority margin. RESULTS: Eighty patients (STEMI, 54 patients [67.5%]) were analyzed. The area under the curve of QCG score was 0.947. Binned at 50 (binary QCG), the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 98.1% (95% confidence interval [CI], 94.6%, 100.0%), 76.9% (95% CI, 60.7%, 93.1%), 89.8% (95% CI, 82.1%, 97.5%) and 95.2% (95% CI, 86.1%, 100.0%), respectively. The difference in sensitivity and specificity between binary QCG and the joint clinical decision was 3.7% (95% CI, -3.5%, 10.9%) and 19.2% (95% CI, -4.7%, 43.1%), respectively, confirming the non-inferiority. The estimated median reduction in D2B time, evaluation cost, and the relative risk of 1-year mortality were 11.0 minutes (interquartile range [IQR], 7.3-20.0 minutes), 26,902.2 KRW (22.78 USD) per STEMI patient, and 12.39% (IQR, 7.51-22.54%), respectively. CONCLUSION: AI-assisted CCL activation using initial ECG is feasible. If such a policy is implemented, it would be reasonable to expect some reduction in D2B time, medical cost, and 1-year mortality.
Assuntos
Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Inteligência Artificial , Serviço Hospitalar de Emergência , Humanos , Infarto do Miocárdio/diagnóstico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Fatores de TempoRESUMO
The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Proteínas de Neoplasias/fisiologia , Proteoma , Reparo de DNA por Recombinação/fisiologia , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/fisiologia , Humanos , Morfolinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Estabilidade Proteica , Pirazinas/farmacologia , Pironas/farmacologia , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Fluxes are the central trait of metabolism and Kinetic Flux Profiling (KFP) is an effective method of measuring them. To generalize its applicability, we present an extension of the method that estimates the relative changes of fluxes using only relative quantitation of 13C-labeled metabolites. Such features are directly tailored to the more common experiment that performs only relative quantitation and compares fluxes between two conditions. We call our extension rKFP. Moreover, we examine the effects of common missing data and common modeling assumptions on (r)KFP, and provide practical suggestions. We also investigate the selection of measuring times for (r)KFP and provide a simple recipe. We then apply rKFP to 13C-labeled glucose time series data collected from cells under normal and glucose-deprived conditions, estimating the relative flux changes of glycolysis and its branching pathways. We identify an adaptive response in which de novo serine biosynthesis is compromised to maintain the glycolytic flux backbone. Together, these results greatly expand the capabilities of KFP and are suitable for broad biological applications.
Assuntos
Análise do Fluxo Metabólico , Metaboloma/fisiologia , Modelos Biológicos , Isótopos de Carbono/metabolismo , Glucose/metabolismo , Glicólise/fisiologia , Cinética , Biologia de SistemasRESUMO
Background: The Laophontidae is a very large and diverse family containing more than 320 species and 74 genera in the Harpacticoida. According to records published until recently, 25 species of 12 genera of Laophontidae were reported to appear in Korean waters. The most common laophontid species in Korean waters is Paralaophontecongenera (Sars, 1908). During research on the meiobenthic community in the subtidal zone near the Korean coast in the East Sea, we found an undescribed genus of the Laophontidae family. The character traits of this undescribed specimen of the Laophontidae family do not match any existing genus. New information: Herein, a new genus of the interstitial marine benthic copepods family Laophontidae T. Scott, 1905 is described from the subtidal zone near Hupo Harbour on the east coast of Korea. This genus was named Strictlaophonte gen. nov. and has been classified into the family Laophontidae. This was based on the presence of seven segmented female antennules, reduced antennary exopod, first endopodal segments having no inner setae from the second leg to the fourth leg and P5 with a distinct exopod that is not fused at the basis. The distinguishing features of Strictlaophonte gen. nov. are P5 exopod having only four setae, the P1 exopod having two segments and the antenna exopod having four setae. In particular, this new genus has unique characteristics in that the caudal rami are very tightly attached to each other.
RESUMO
As the economic burden associated with vision loss and ocular damage continues to rise, there is a need to explore novel treatment strategies. Extracellular vesicles (EVs) are enriched with various biological cargo, and there is abundant literature supporting the reparative and immunomodulatory properties of stem cell EVs across a broad range of pathologies. However, one area that requires further attention is the reparative effects of stem cell EVs in the context of ocular damage. Additionally, most of the literature focuses on EVs isolated from primary stem cells; the use of EVs isolated from human telomerase reverse transcriptase (hTERT)-immortalized stem cells has not been thoroughly examined. Using our large-scale EV-manufacturing platform, we reproducibly manufactured EVs from hTERT-immortalized mesenchymal stem cells (MSCs) and employed various methods to characterize and profile their associated cargo. We also utilized well-established cell-based assays to compare the effects of these EVs on both healthy and damaged retinal pigment epithelial cells. To the best of our knowledge, this is the first study to establish proof of concept for reproducible, large-scale manufacturing of hTERT-immortalized MSC EVs and to investigate their potential reparative properties against damaged retinal cells. The results from our studies confirm that hTERT-immortalized MSC EVs exert reparative effects in vitro that are similar to those observed in primary MSC EVs. Therefore, hTERT-immortalized MSCs may represent a more consistent and reproducible platform than primary MSCs for generating EVs with therapeutic potential.
Assuntos
Células Epiteliais , Vesículas Extracelulares , Células-Tronco Mesenquimais , Epitélio Pigmentado da Retina , Telomerase , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Humanos , Vesículas Extracelulares/metabolismo , Telomerase/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/citologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/citologiaRESUMO
Mitigating sepsis-induced severe organ dysfunction with magnetic nanoparticles has shown remarkable advances in extracorporeal blood treatment. Nevertheless, treating large septic animals remains challenging due to insufficient magnetic separation at rapid blood flow rates (>6 L h-1) and limited incubation time in an extracorporeal circuit. Herein, superparamagnetic nanoclusters (SPNCs) coated with red blood cell (RBC) membranes are developed, which promptly capture and magnetically separate a wide range of pathogens at high blood flow rates in a swine sepsis model. The SPNCs exhibited an ultranarrow size distribution of clustered iron oxide nanocrystals and exceptionally high saturation magnetization (≈ 90 emu g-1) close to that of bulk magnetite. It is also revealed that CD47 on the RBCs allows the RBC-SPNCs to remain at a consistent concentration in the blood by evading innate immunity. The uniform size distribution of the RBC-SPNCs greatly enhances their effectiveness in eradicating various pathogenic materials in extracorporeal blood. The use of RBC-SPNCs for extracorporeal treatment of swine infected with multidrug-resistant E. coli is validated and found that severe bacteremic sepsis-induced organ dysfunction is significantly mitigated after 12 h. The findings highlight the potential application of RBC-SPNCs for extracorporeal therapy of severe sepsis in large animal models and potentially humans.
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Nanopartículas de Magnetita , Sepse , Animais , Sepse/terapia , Suínos , Nanopartículas de Magnetita/química , Eritrócitos , Insuficiência de Múltiplos Órgãos/terapia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Modelos Animais de Doenças , Infecções por Escherichia coli/terapia , Nanopartículas Magnéticas de Óxido de Ferro/química , Escherichia coliRESUMO
The present paper deals with description of three new marine gastrotrich species belonging to the genus Tetranchyroderma with a new record for Korea of T schizocirratum Chang, Kubota & Shirayama, 2002, on the basis of specimens from the Korean coast. Tetranchyroderma anisoankyrum sp. nov. is differentiated from congeners by its dorsal cuticular armature of pentancres with central tine longer than the others, a pair of rod-like cephalic tentacles, 2 cirratum-type TbDL, 13-14 cirratum-type TbL per side, and a pair of TbL. Tetranchyroderma coreense sp. nov. is distinguished from other pentancrous species by cirratum-type tubes of 2 TbDL, one TbL, 3-4 TbVL, paired foot-type TbV, and absence of cephalic tentacles. Tetranchyroderma oblongum sp. nov. is characterized by the character combination of cuticular armature of tetrancres, 7 dorsolateral and 7-9 lateral cirratum-type tubes, and 33-38 TbVL along whole body. This brings the total number of species in the genus Tetranchyroderma known from South Korea to 12.
Assuntos
Eucariotos/classificação , Estruturas Animais/anatomia & histologia , Estruturas Animais/crescimento & desenvolvimento , Animais , Tamanho Corporal , Eucariotos/crescimento & desenvolvimento , Tamanho do Órgão , República da CoreiaRESUMO
A new kinorhynch species, Dracoderes nidhug nov. sp., is described from the East Sea, at 160 m depth, off Uljin, Korea. The new species is the fourth that can be assigned to the genus, and is recognized by the presence of dorsal spines on segments 3 to 9 (alternatingly displaced to more paradorsal positions on segments 3 to 8), subdorsal tubules on segment 2, lateroventral tubules on segments 2, 5 and 10, and lateral accessory tubules on segment 8. The new species shows two longitudinal, intracuticular markings on the ventral side of segment 1, which could be interpret as rudimentary plate joints, corresponding to the articulations found on the sternal plates of segment 1 in species of Pycnophyes and Kinorhynchus. The finding brings further support to a closer relationship between Dracoderes and homalorhagid kinorhynchs.
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Invertebrados/anatomia & histologia , Invertebrados/classificação , Animais , Feminino , Invertebrados/ultraestrutura , Masculino , Microscopia Eletrônica de Varredura , República da CoreiaRESUMO
Objective: We examined the change in foreleg raising power after Sion's local paralysis (SLP) with succinylcholine in the shoulder muscle. Methods: A randomized, double blind, placebo-controlled, porcine study was designed and performed at a research institution. Ten male Korean native pigs were randomized into an intervention group (n = 5) and a control group (n = 5). The injection points were in the middle of the left trapezius muscle and the middle of the left deltoid muscle. The control group received 2 ml normal saline (NS), 1 ml injected in each point. The intervention group received 0.4 mg/kg succinylcholine diluted to 2 ml in NS, and 1 ml was injected in each point. To represent the foreleg raising power, the height of the left forelegs from baseline (experiment table) was measured. We measured the foreleg height and oxygen saturation at -4, -2, 0, +2, +4, +6, +8, +10, +20, +30, and +60 min. Results: After SLP, foreleg height immediately declined in the intervention group. It recovered slightly for a few minutes and declined from 4 to 8 min. In the control group, foreleg height was relatively similar throughout the study period. A repeated-measure analysis of variance revealed a significant group × time interaction (F10,80 = 2.37, P = 0.017), a significant main effect for group (F1,8 = 6.25, P = 0.037), and a significant main effect for time (F10,80 = 4.41, P < 0.001). Post hoc analysis demonstrated that the intervention group showed significantly less foreleg raising power than the control group at 0, 4, 6, 8, 20, and 30 min (P < 0.05). Conclusions: Compared with the control group, the foreleg raising power in the intervention group immediately decreased significantly and persisted for a period after SLP, without hypoxia, in a pig model.
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The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).
Assuntos
Produtos Biológicos , Ciclofilina A , Imunofilinas , Chaperonas Moleculares , Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Cisteína/química , Cisteína/genética , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais , Ciclofilina A/química , Ciclofilina A/metabolismo , Imunofilinas/química , Imunofilinas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
We demonstrate a novel method that employs a frame-accumulation and shaped-function technique to improve an image sensor's detection sensitivity using probability statistics. It can obtain the unbiased estimate for the low-light-level image signal, thus upgrading the signal-to-noise ratio to a high degree. It was verified by an experiment in a sealed box. By the help of a variable light beam-shaped function saw-tooth signal in front of a camera, the low-light-level shadow image that was invisible to the camera could be revealed clearly from the frame accumulation data. The method can surpass an image sensor's detection limitation.