Herein, the determination of chlordimeform and its metabolite 4-chloro-2-methylaniline residue in milk was performed for the first time using gas chromatography-tandem mass spectrometry (GC-MS/MS). Samples were extracted using acetonitrile, and cleaned using a quick, easy, cheap, effective, rugged, and safe (QuEChERS) method. Separation was performed using the DB-17 MS column. It was detected in a selected reaction monitoring (SRM) mode and quantified using a matrix-matched isotope internal standard method. Under optimal conditions, a good linear relationship was observed in the concentration range of 10-200 µg/kg. The limit of quantitation was 10.0 µg/kg. The spiked recoveries for the target substance ranged from 84.5 % to 107.3 %, with relative standard deviations (RSD) of <7.2 %. The spiked samples were further confirmed by gas chromatography-quadrupole-Orbitrap high-resolution mass spectrometry (GC-Orbitrap HRMS). The combined method resulted in high accuracy and sensitivity and was suitable for the determination of chlordimeform and its metabolite 4-chloro-2-methylaniline residue in milk.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

BACKGROUND: As cyanide (CN-) is a significant hazard to the environment and human health, it is essential to monitor cyanide levels in water and food samples. Moreover, real-time visualization of CN-could provide an additional understanding of its critical physiological and toxicological roles in living cells. The fluorescence approach based on small organic probes is an effective way for the detection of CN-. In this approach, a triphenylamine-xhantane conjugate was applied to detect in many samples such as sewage water, soil, sprouted potato, apricot seed, and living cells.
RESULTS: We report a new ratiometric near-infrared fluorescent probe based on a triphenylamine-xhantane derivative for CN-sensing in many samples. The probe displays high selectivity for only CN- ions among a series of analytes. The addition of cyanide to the dicyanovinyl moiety of the probe disrupts π-conjugation followed by the interruption of internal charge transfer. Consequently, the emission peak of the probe shifts hypsochromically from 655 to 495 nm. There is a linear correlation between the emission intensity (I495) and cyanide level, with a detection limit of 0.036 μM. The probe has many advantages over many probes, such as NIR fluorescence, ratiometric response, low cytotoxicity (85.0 % cell viability up to 50.0 μM of the probe), good membrane permeability, fast response time (4.0 min), high selectivity, good photostability, and anti-interference capability.
CONCLUSIONS: Although various probes have been reported in the literature, the use of triphenylamine-xhantane unit as CN- probe has yet to be explored. The probe can detect trace levels of cyanide in many samples such as sewage water, soil, sprouted potatoes, and apricot seeds. Furthermore, it is successfully utilized for the ratiometric fluorescent bioimaging of cyanide in living cells.

暂无摘要。

Non-small cell lung cancer (NSCLC) is characterized by high recurrence rates in the early stages. In a German cohort, recurrence-free survival after 5 years was 62% (stage IA1), 40.7% (stage IIA) and 28% (stage IIIA). In addition to the perioperative use of immune checkpoint inhibitors, targeted tumor therapy is also making inroads as an innovation from the palliative setting into the early stages. Of particular relevance is the use of the EGFR inhibitor osimertinib, which has been shown to improve overall survival in the adjuvant setting. In this practice-oriented review, we briefly describe the current status of adjuvant targeted therapy and the associated testing and provide an outlook on further developments.
Das nicht kleinzellige Lungenkarzinom (NSCLC) fällt durch hohe Rezidivraten in den Frühstadien auf. In einer deutschen Kohorte lag das rezidivfreie Überleben nach 5 Jahren bei 62% (Stadium IA1), 40,7% (Stadium IIA) und 28% (Stadium IIIA). Neben dem perioperativen Einsatz von Immuncheckpointinhibitoren drängt auch die zielgerichtete Tumortherapie als Innovation aus dem palliativen Setting in die frühen Stadien. Von besonderer Relevanz ist der Einsatz des EGFR-Inhibitors Osimertinib (EGFR: Epidermal Growth Factor Receptor), für den eine Verbesserung des Gesamtüberlebens in der adjuvanten Situation gezeigt wurde. In dieser praxisorientierten Übersichtarbeit beschreiben wir kurz den aktuellen Stand der adjuvanten zielgerichteten Therapie und der dazugehörigen Testung und geben einen Ausblick auf weitere Entwicklungen.

This study investigated the earliest change of cerebral blood flow (CBF) and its relationship with β-amyloid (Aβ) burden in preclinical Alzheimer\'s disease (AD) employing dual-phase 18F-florbetaben (FBB) PET. Seventy-one cognitively normal (NC) individuals were classified as Aβ negative (Aβ-NC) or positive (Aβ+NC) based on two different cutoff values: an SUVR of > 1.08 and a Centiloid scale of > 20. The PET scans were acquired in two phases: an early phase (0-10 min, eFBB) and a delayed phase (90-110 min, dFBB), which were averaged to generate single-frame images for each phase. Furthermore, an R1 parametric map was generated from the early phase data using a simplified reference tissue model. We conducted regional and voxel-based analyses to compare the eFBB, dFBB, and R1 images between the Aβ positive and negative groups. In addition, the correlations between the CBF proxy R1 and the dFBB SUVR were analyzed. The Aβ+NC group showed significantly higher dFBB SUVR in both the global cerebral cortex and target regions compared to the Aβ-NC group, while no significant differences were observed in eFBB SUVR between the two groups. Furthermore, the Aβ+NC group exhibited significantly higher R1 values, a proxy for cerebral perfusion, in both the global cerebral cortex and target regions compared to the Aβ-NC group. Significant positive correlations were observed between R1 and dFBB SUVR in both the global cerebral cortex and target regions, which remained significant after controlling for demographics and cognitive profiles, except for the medial temporal and occipital cortices. The findings reveal increased CBF in preclinical AD and a positive correlation between CBF and amyloid pathology. The positive correlation between R1 and amyloid burden may indicate a compensatory mechanism in the preclinical stage of Alzheimer\'s disease, but to elucidate this hypothesis, further longitudinal observational studies are necessary.

A LOx-based electrochemical biosensor for high-level lactate determination was developed. For the construction of the biosensor, chitosan and Nafion layers were integrated by using a spin coating procedure, leading to less porous surfaces in comparison with those recorded after a drop casting procedure. The analytical performance of the resulting biosensor for lactate determination was evaluated in batch and flow regime, displaying satisfactory results in both modes ranging from 0.5 to 20 mM concentration range for assessing the lactic acidosis. Finally, the lactate levels in raw serum samples were estimated using the biosensor developed and verified with a blood gas analyzer. Based on these results, the biosensor developed is promising for its use in healthcare environment, after its proper miniaturization. A pH probe based on common polyaniline-based electrochemical sensor was also developed to assist the biosensor for the lactic acidosis monitoring, leading to excellent results in stock solutions ranging from 6.0 to 8.0 mM and raw plasma samples. The results were confirmed by using two different approaches, blood gas analyzer and pH-meter. Consequently, the lactic acidosis monitoring could be achieved in continuous flow regime using both (bio)sensors.

BACKGROUND: Both 11C-Pittsburgh compound-B (PiB) and 18F-Flutemetamol (FMT) have off-target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid-β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid-β evaluations.
METHODS: A cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54-84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB-PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut-off of 22.
RESULTS: PiB and FMT visual positivity agreed with quantitative positivity on PiB-based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid-β positive) and centiloid (amyloid-β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups.
CONCLUSIONS: Disagreements between amyloid-β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near-threshold cortical uptake, especially with FMT.

BACKGROUND: Amyloid-negative amnestic mild cognitive impairment (MCI) patients have a conversion rate to dementia of approximately 10% within 2 years. This study aimed to investigate whether brain age, calculated using quantitative data obtained from brain magnetic resonance imaging (MRI) artificial intelligence (AI) software can be an important factor in predicting the conversion of dementia in amyloid-negative amnestic MCI patients.
METHODS: We conducted a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain MRI, and [18F]-florbetaben (FBB) positron emission tomography (PET) scan. Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Brain age was determined through volumetric assessment of 12 distinct brain regions using commercially available segmentation software, Neurophet AQUA.
RESULTS: During the follow-up period, 38% (35/91) of patients converted to dementia from amnestic MCI. 73% (66/91) of patients had a higher brain age than their actual chronological age. In the conversion group, all participants except three (91%, 32/35) had a brain age older than their chronological age. Conversely, the conversion rate to dementia was significantly lower in the group with a younger brain age than their actual age. The subjects were divided into eight groups based on sex, education level, and brain age. When defining the \'survival\' as the non-conversion of MCI to dementia, these groups significantly differed in survival probability with a p-value of 0.036. The low-educated female group with a higher brain age than their actual age had the lowest survival rate of all groups.
CONCLUSIONS: Our findings suggest that MRI-based brain age used in this study can contribute to predicting conversion to dementia in patients with amyloid-negative amnestic MCI.

BACKGROUND: First- and second-generation anti-epithelial growth factor receptor tyrosine kinase inhibitors have shown great efficacy in the treatment of advanced adenocarcinoma with epithelial growth factor receptor mutations, but this efficacy is limited by certain resistance mechanisms, in particular the T790M mutation, which must be screened before second-line treatment with osimertinib is indicated. The search for this mutation is sometimes difficult, especially in cases of intracranial relapse, through this case report we attempt to discuss the possibility of initiating treatment with osimertinib despite an unknown T790M mutation in such situation.
METHODS: We present the case of a 70-year-old Moroccan male patient diagnosed with non-small cell lung carcinoma initially metastatic to the pleura with an epithelial growth factor receptor mutation who received gefitinib in first line with a complete response, he subsequently presented with cerebral oligo-progression with extra cranial stability. The patient was started on osimertinib with unknown T790M status, as it was impossible to perform a cerebral biopsy, the evolution was characterized by a partial response followed by stereotactic radiotherapy then a complete response for 2 years.
CONCLUSIONS: We can discuss osimertinib as an option for patients with stage IV non-small cell lung cancer with brain oligo-progression on prior tyrosine kinase inhibitors and unknown T790M status, further studies are needed in this area.