The v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene is one of the most critical proto-oncogenes and functions as a key regulator in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. Currently, the combination of Dabrafenib and Trametinib has been recommended as first-line therapy for BRAF V600-mutant NSCLC by multiple domestic and international guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and Chinese Society of Clinical Oncology (CSCO). However, there are no clear targeted treatment recommendations for BRAF non-V600 mutations. Although case reports suggest that Dabrafenib combined with Trametinib may be effective for patients with BRAF non-V600 mutations, the efficacy and safety require further validation due to limited sample size and lack of large-scale clinical trial data. This article reports a case of NSCLC with a rare BRAF insertion and deletion mutation that responded well to the treatment of Dabrafenib in combination with Trametinib, aiming to enhance clinicians' understanding of such NSCLC cases with extremely rare mutation and provide a reference for future treatment strategies.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Imidazoles/administration & dosage* ; Lung Neoplasms/pathology* ; Mutation ; Neoplasm Metastasis ; Oximes/administration & dosage* ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics* ; Pyridones/administration & dosage* ; Pyrimidinones/administration & dosage*

Infant, Newborn ; Humans ; Imidazoles/therapeutic use* ; Oximes/therapeutic use*

Although methidathion is an organophosphate insecticide, it is different from the other organophosphates in terms of toxicity. Because of its relatively high fat solubility, the apparent volume of methidathion distribution throughout the body is very high, indicating that hemoperfusion is not effective in removing this organophosphate from the body. Redistribution of methidathion from fat to blood can also occur when plasma levels diminish. Additionally, acetylcholinesterase aging, which is the loss of an alkyl side chain that prevents reactivation by oximes, is very rapid so that the effective reactivation by oximes is thwarted. Thus, methidathion's effect on acetylcholinesterase inhibition is long lasting, particularly with a high dose. In addition to its parasympatholytic effect and ability to induce muscle paralysis, methidathion poisoning is associated with a profound and long-lasting circulatory collapse due to sympathetic ganglion blockade. This report presents the case of a 55-year-old man who accidentally ingested a high dose of methidathion. He later developed enteroinvasive aspergillosis infection-induced multiple bowel perforations on two separate occasions while on mechanical ventilator support, resulting in a fatal outcome. The renin-angiotensin axis activated by sympathetic ganglion blockade may have reduced the patient's splanchnic blood flow, contributing to translocation of endotoxin. Also, the effect of excessive acetylcholine on non-neuronal acetylcholine receptors may have contributed to the development of fatal enteroinvasive aspergillosis in this patient.
Acetylcholine ; Acetylcholinesterase ; Aging ; Aspergillosis ; Fatal Outcome ; Ganglia ; Ganglia, Sympathetic ; Hemoperfusion ; Humans ; Middle Aged ; Organophosphate Poisoning ; Organophosphates ; Oximes ; Paralysis ; Parasympatholytics ; Plasma ; Poisoning* ; Receptors, Cholinergic ; Shock ; Solubility ; Ventilators, Mechanical

Although methidathion is an organophosphate insecticide, it is different from the other organophosphates in terms of toxicity. Because of its relatively high fat solubility, the apparent volume of methidathion distribution throughout the body is very high, indicating that hemoperfusion is not effective in removing this organophosphate from the body. Redistribution of methidathion from fat to blood can also occur when plasma levels diminish. Additionally, acetylcholinesterase aging, which is the loss of an alkyl side chain that prevents reactivation by oximes, is very rapid so that the effective reactivation by oximes is thwarted. Thus, methidathion's effect on acetylcholinesterase inhibition is long lasting, particularly with a high dose. In addition to its parasympatholytic effect and ability to induce muscle paralysis, methidathion poisoning is associated with a profound and long-lasting circulatory collapse due to sympathetic ganglion blockade. This report presents the case of a 55-year-old man who accidentally ingested a high dose of methidathion. He later developed enteroinvasive aspergillosis infection-induced multiple bowel perforations on two separate occasions while on mechanical ventilator support, resulting in a fatal outcome. The renin-angiotensin axis activated by sympathetic ganglion blockade may have reduced the patient's splanchnic blood flow, contributing to translocation of endotoxin. Also, the effect of excessive acetylcholine on non-neuronal acetylcholine receptors may have contributed to the development of fatal enteroinvasive aspergillosis in this patient.
Acetylcholine ; Acetylcholinesterase ; Aging ; Aspergillosis ; Fatal Outcome ; Ganglia ; Ganglia, Sympathetic ; Hemoperfusion ; Humans ; Middle Aged ; Organophosphate Poisoning ; Organophosphates ; Oximes ; Paralysis ; Parasympatholytics ; Plasma ; Poisoning ; Receptors, Cholinergic ; Shock ; Solubility ; Ventilators, Mechanical

PURPOSE: Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis. MATERIALS AND METHODS: Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg.kg-1.d-1) and high-dose darapladib (50 mg.kg-1.d-1) interventions were then administered over the course of 2 weeks. RESULTS: The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05). CONCLUSION: Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.
1-Alkyl-2-acetylglycerophosphocholine Esterase/*antagonists & inhibitors/blood/drug effects ; Animals ; Atherosclerosis/blood/*drug therapy/*enzymology ; *Benzaldehydes ; C-Reactive Protein/metabolism ; Cholesterol/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Dose-Response Relationship, Drug ; Male ; *Oximes ; Phospholipase A2 Inhibitors/*administration & dosage/adverse effects ; Rats ; Rats, Sprague-Dawley ; Triglycerides/blood ; rho-Associated Kinases/*metabolism

In a continuation of our studies to discover bioactive secondary metabolites from marine sources, we further investigated samples from a tryptamine and phenyl-alkane producing sponge, which resulted in the isolation of four uncommon small molecules and five nucleosides. Their structures were determined to be 7,8-dihydroimidazo[1,5-c]pyrimidin-5(6H)-one (1), 5-chlorocavernicolin (2), maleimide-5-oxime (3), 3-methylmaleimide-5-oxime (4), uridine (5), 2'-deoxyuridine (6), thymidine (7), adenine (8), and adenosine (9) by spectroscopic analyses. The isolated compounds were evaluated for inhibitory activity against soluble epoxide hydrolase (sEH) as well as the Wnt/beta-catenine signaling pathway.
Adenine ; Adenosine ; Nucleosides* ; Oximes* ; Porifera* ; Thymidine ; Uridine

Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π-π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
Apoptosis ; drug effects ; Cell Line, Tumor ; Enzyme Activation ; drug effects ; Humans ; Ligands ; Molecular Docking Simulation ; Nuclear Receptor Subfamily 4, Group A, Member 1 ; genetics ; metabolism ; Oximes ; metabolism ; pharmacology ; Protein Conformation ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyrazoles ; metabolism ; pharmacology ; Retinoid X Receptor alpha ; chemistry ; genetics ; metabolism ; Thiazoles ; metabolism ; pharmacology ; Transcription, Genetic ; drug effects ; Transcriptional Activation ; drug effects ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUNDMultidrug resistance (MDR) is a main reason for paclitaxel (TAX) treatment failure. Indirubin-3'-monoxime (IRO) and Matrine are traditional Chinese medicines, which may reverse the resistance of tumor cells to some chemotherapy drugs, but the relationship between paclitaxel resistance and Matrine is still unclear. The aim of this study was to explore the potential molecular mechanism of IRO and Matrine in reversal of TAX resistance.

METHODSIn this study, MTT assay was used to measure the non-cytotoxic dosage of IRO and Matrine on NCI-H520/TAX25 cells and determine the reversal extent of TAX resistance under non-toxic doses. In addition, RT-PCR and Western blotting were used to evaluate the mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 cells using semi-quantitative methods.

RESULTSThere was no obvious inhibition on sensitive cell strains and drug-resistant strains, when the final concentration was at lest 4 µmol/L for IRO and 100 µmol/L for Matrine. So 4 µmol/L of IRO and 100 µmol/L of Matrine were considered as the reversal dosage. When 4 µmol/L of IRO or 100 µmol/L of Matrine were used together with TAX, the sensitivity to TAX increased evidently in NCI-H520/TAX2 cells; the reversal rate of IRO and Matrine was about 1.92 (43.56/22.6 nmol/L) and 1.74 (43.56/25.0 nmol/L), respectively. The mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 decreased significantly (P < 0.05) after addition of IRO or Matrine in TAX treatment, compared to that of TAX treatment alone.

CONCLUSIONThe decrease in both mRNA expression and protein level of survivin, Oct-4, and Sox-2 might be the molecular mechanism, by which IRO and Matrine mediate the reversal of TAX resistance.

Alkaloids ; pharmacology ; Blotting, Western ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Humans ; Indoles ; pharmacology ; Inhibitor of Apoptosis Proteins ; genetics ; metabolism ; Octamer Transcription Factor-3 ; genetics ; metabolism ; Oximes ; pharmacology ; Paclitaxel ; pharmacology ; Quinolizines ; pharmacology ; SOXB1 Transcription Factors ; genetics ; metabolism

Asoprisnil, a member of the selective progesterone receptor modulators, exerts high progesterone receptor selectivity, endometrial targeted advantages and significant anti-implantation effect in rats. The purpose of this study was to confirm the anti-implantation effect of asoprisil, investigate the ultrastructural changes of the peri-implantation endometrium in mice and explore the effect of asoprisnil on endometrial receptivity and its targeted contraceptive proficiency. Post-coitus mice were administered with different dosages (0.2, 0.1, 0.05 mg·g(-1)·day(-1)) of asoprisnil from day 1 of pregnancy to day 3. Then 3 animals in each group were killed on day 5 of pregnancy, and uteri were collected to examine the ultrastructural changes of endometria under a transmission electron microscope (TEM). A total of 80 animals were sacrificed on day 8 of pregnancy, and the uterine horns were examined for the presence or absence of nidation sites and the number of implantation embryos. The results showed that the implantation rate and the average number of implantation embryos in asoprisnil groups were statistically significantly decreased as compared with the vehicle control group (P<0.05). The TEM results revealed that, in vehicle control group, the tight junction between the luminal epithelia cells was short and straight, the gap was wide; the luminal epithelia cells were covered with plenty of short, clavate and neatly arranged microvilli; the endometril stromal cells were large with plenty of cytoplasm, and showed significant decidual change; there was more than one nucleus in stromal cells, and the karyotheca was integrity. In low dosage and high dosage asoprisnil groups, the tight junction was longer and more curve than in the vehicle control group; microvilli were uneven and asymmetrically distributed in luminal epithelia; the stromal cells were small and the decidual change was not significant; there were karyopyknosis and karyolysis in stromal cells; there were abnormal thick-wall vessels in the endometrium. It was suggested that asoprisnil changed the ultrastructure of the endometrium in implantation window, disturbed the endometrial receptivity and finally resulted in embryo implantation failure.
Animals ; Contraception, Postcoital ; methods ; Embryo Implantation, Delayed ; drug effects ; physiology ; Endometrium ; drug effects ; physiology ; ultrastructure ; Estrenes ; administration & dosage ; Female ; Mice ; Oximes ; administration & dosage ; Oxytocics ; administration & dosage ; Pregnancy ; Pregnancy, Animal ; Treatment Outcome

BACKGROUND: Spectacle contact allergy is not infrequent. The fine scratches on the spectacle frames which may play a role in the sensitization to the potential allergenic components have not been studied. OBJECTIVE: We sought the relationship between the scratches on the spectacle frames and the allergic contact dermatitis (ACD) in the Republic of Korea. METHODS: A total of 42 Korean patients with ACD at the spectacle contact sites were enrolled. Their spectacle frames were examined with the dimethylglyoxime (DMG) test and analyzed by the scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). Patch tests (thin-layer rapid use epicutaneous test [TRUE tests]) were performed to identify the skin allergens. RESULTS: The DMG-positive spectacle frames were identified in 78.5% of the frames. The SEM results showed that there were more scratches on the skin-contacting parts of the spectacle frames than the non-skin-contacting parts of the same frames. In the EDS findings, the mean nickel content (weight, %) of the spectacle frames was 15.7+/-5.5, and the mean chromium content was 20.3+/-3.4 at the skin-contacting parts. In the TRUE tests, nickel sulphate was the most common allergen (31 cases, 73.8%), and potassium dichromate was the second (9 cases, 21.4%). Three patients presented simultaneous positive reactions with nickel sulphate and potassium dichromate. CONCLUSION: Minor visible and non-visible fine scratches on the spectacle frames may present the provocation factors of the ACD. Nickel sulphate was the most common allergen suspected of provoking the spectacle frame-induced ACD, followed by potassium dichromate.
Chromium ; Dermatitis, Allergic Contact ; Humans ; Hypersensitivity ; Microscopy, Electron, Scanning ; Nickel ; Oximes ; Patch Tests ; Potassium ; Potassium Dichromate ; Skin ; Spectrum Analysis