Predicting the optimal concentration of remifentanil for skull pin fixation with hemodynamic and analgesia nociception index monitoring.

Inadequate antinociception during skull pin fixation may cause hemodynamic instability in intracranial surgery. The optimal concentration of remifentanil to provide adequate antinociception and stable hemodynamics during skull pin fixation under analgesia nociception index monitoring is unknown. This study is to assess the 90% effective concentration of remifentanil for skull pin fixation under hemodynamic and analgesia nociception index monitoring. Twenty-six patients were enrolled for intracranial surgery, anesthesia was induced and maintained under total intravenous anesthesia using target-controlled infusion for remifentanil and propofol under analgesia nociception index and bispectral index monitoring. Skull pin fixation was performed at different effect-site concentrations of remifentanil required for Dixon's up-and-down method with a step size of 0.5 ng/ml under bispectral index 40-60. Inadequate antinociception is defined when either ANI < 30 or > 20% in hemodynamic changes from baseline (e.g. heart rate > 100 beats/min, or blood pressure > 180/100 mmHg) and the effect-site concentration of remifentanil is considered as failure. It is considered success as ANI > 30 and < 20% hemodynamic changes from baseline simultaneously. Seven pairs of failure/success were used for probit analysis. The 90% effective concentration of remifentanil for skull pin fixation with adequate antinociception and hemodynamic stability was 4.7 ng/ml.

Dual antibody-aided mesoporous nanoreactor for H2O2 self-supplying chemodynamic therapy and checkpoint blockade immunotherapy in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents a formidable challenge due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, rendering it unresponsive to conventional hormonal and targeted therapies. This study introduces the development of mesoporous nanoreactors (NRs), specifically mPDA@CuO2 NRs, as acid-triggered agents capable of self-supplying H2O2 for chemodynamic therapy (CDT). To enhance therapeutic efficacy, these NRs were further modified with immune checkpoint antagonists, specifically anti-PD-L1 and anti-CD24 antibodies, resulting in the formation of dual antibody-aided mesoporous nanoreactors (dAbPD-L1/CD24-mPDA@CuO2 NRs). These NRs were designed to combine CDT and checkpoint blockade immunotherapy (CBIT) for precise targeting of 4T1 TNBC cells. Remarkably, dAbPD-L1/CD24-mPDA@CuO2 NRs exhibited tumor-targeted CDT triggered by H2O2 and successfully activated immune cells including T cells and macrophages. This integrated approach led to a remarkable inhibition of tumor growth by leveraging the collaborative effects of the therapies. The findings of this study introduce a novel and promising strategy for the integrative and collaborative treatment of refractory cancers, providing valuable insights into addressing the challenges posed by aggressive breast cancer, particularly TNBC.

Unlocking Synergistic Potential: Enhancing Regorafenib Efficacy in Hepatocellular Carcinoma Through Combination Therapy With 18ß-Glycyrrhetinic Acid.

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a primary liver cancer with limited treatment options and poor prognosis. Regorafenib, a multi-kinase inhibitor, has shown promise in HCC treatment; however, its efficacy can be enhanced by combining it with other agents. 18ß-glycyrrhetinic acid (18ß-gly) is a natural compound with potential anti-cancer properties. MATERIALS AND METHODS: The toxicity and mechanism of regorafenib and 18ß-gly was assessed on Hep3B cells, Huh7 cells, and Hep3B bearing animal model. RESULTS: The combination of regorafenib and 18ß-gly exhibited synergistic toxicity in HCC cells and animal model. Importantly, no significant differences in body weight or major tissue damage were observed after treatment with the combination of two drugs. Furthermore, the combination treatment modulated apoptosis-related markers and the mTOR signaling pathway. CONCLUSION: The study provides evidence for the synergistic effect of 18ß-gly and regorafenib in a HCC model. The combination treatment modulated apoptosis-related markers and the mTOR signaling pathway, highlighting potential mechanisms underlying its therapeutic efficacy.

Imipramine Suppresses Tumor Growth and Induces Apoptosis in Oral Squamous Cell Carcinoma: Targeting Multiple Processes and Signaling Pathways.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) has limited treatment options. This study investigated imipramine, a tricyclic antidepressant, as a potential therapy for OSCC using a SAS-bearing xenograft animal model. MATERIALS AND METHODS: The SAS-bearing xenograft model evaluated imipramine's impact on tumor growth. The control group received no treatment, while the imipramine-treated group received regular doses. Tumor growth, confirmed by imaging, and histological analysis assessed size and weight. Imipramine's effects on apoptosis, epithelial-to-mesenchymal transition (EMT), and transcription factors (AKT, ERK, STAT3) were analyzed. RESULTS: Imipramine significantly suppressed tumor growth within 6 days of treatment, with sustained activity. Computer tomography (CT) scans and histology confirmed reduced size and weight by imipramine. Imipramine induced apoptosis via caspase-dependent/-independent pathways, inhibited EMT, and down-regulated phosphorylated AKT, ERK, and STAT3. CONCLUSION: Imipramine shows promise as an effective OSCC therapy, inhibiting tumor growth, inducing apoptosis, and inhibiting EMT. Its impact on transcription factors and modulation of the AKT/ERK/STAT3 pathway suggest a multifaceted approach.

Low PTEN expression and overexpression of phosphorylated AktSer473 and AktThr308 are associated with poor overall survival in upper tract urothelial carcinoma.

The PI3K/Akt signaling pathway serves an essential role in various cellular processes, including cell growth, survival, cell motility, angiogenesis and cell metabolism. Loss of PTEN expression and hyperactivation of Akt can result in tumorigenesis. Previous studies observed expression of the Akt protein and absence of the PTEN protein in bladder cancer and non-small cell lung carcinoma tissues. The aim of the present study was to evaluate the expression status and prognostic value of PTEN and the PI3K/Akt signaling pathway in Taiwanese patients with upper tract urothelial carcinoma (UTUC). Archival formalin-fixed, paraffin-embedded (FFPE) tissues from 65 UTUC cases were stained via immunohistochemistry for PTEN, phosphorylated (p)Akt serine (Ser)473 and pAkt threonine (Thr)308. The expression levels of each protein were significantly correlated with clinicopathological parameters. PTEN, pAktSer473 and pAktThr308 protein expression levels were higher in adjacent normal tissues compared with those in tumor tissues. Cytoplasmic PTEN protein expression levels were lower in high-stage tumors compared with those in low-stage tumors, and nuclear and cytoplasmic pAktThr308 protein expression levels were higher in high-grade tumors compared with those in low-grade tumors. Univariate analysis showed that high pathological tumor stage (pT2-4) [P=0.01; hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.34-8.60], metastatic status (P=0.003; HR=3.55, 95% CI, 1.55-8.11), low cytoplasmic PTEN protein expression levels (P=0.016; HR=3.14; 95% CI, 1.24-7.95) and high cytoplasmic pAktSer473 protein expression levels (P=0.019, HR=2.71, 95% CI, 1.18-6.21) were predictive of poor overall survival. However, only metastatic status (P=0.031; HR=2.73; 95% CI, 1.10-6.78), low cytoplasmic PTEN protein expression levels (P=0.017; HR=3.29; 95% CI, 1.24-8.73) and high cytoplasmic pAktSer473 protein expression levels (P=0.027; HR=2.64; 95% CI, 1.12-6.23) remained significant in the multivariate analysis. Kaplan-Meier survival analysis showed that high T stage, metastasis, low expression levels of cytoplasmic PTEN protein and high expression levels of cytoplasmic pAktSer473 protein were significantly associated with poor survival (P=0.006, 0.001, 0.011 and 0.014, respectively). Co-expression of PTENlow/pAktSer473/high and pAktThr308/high phenotypes was associated with a less favorable overall survival (P=0.001). Overall, the present findings demonstrated that low expression levels of PTEN and high expression levels of pAktSer473 and pAktThr308 were predictors for poor overall survival in patients with UTUC.

A new lateral flow plasmonic biosensor based on gold-viral biomineralized nanozyme for on-site intracellular glutathione detection to evaluate drug-resistance level.

Temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) cells would have abnormal redox status due to bio-thiols, like glutathione (GSH), which constitute the most crucial defense system that protects cells from therapeutic agents. Current strategies for GSH detection often require sophisticated instruments that may not be available in laboratories with fewer resources. Here, we circumvent this problem by introducing a lateral flow plasmonic biosensor (LFPB) based on gold-viral biomineralized nanoclusters (AuVCs) as nanozymes that enables the detection of a few molecules with the naked eye and quantified by an auto-analysis software. The GSH level controls the growth of gold nanoparticles (AuNPs) and generates coloured patterns with distinct tonality, which are then auto-analyzed to calculate the GSH concentrations by smartphone with an auto-analysis software. Under the optimized conditions, grayscale value plotted against GSH concentration exhibited a linear relationship within the range of 25-500 µM with a limit of detection (LoD) of 9.80 µM and highly positive correlation between detected GSH level and TMZ drug-resistance level in GBM cells. This excellent property allowed our approach to be used for on-site determination of GSH levels in a rapid (i.e., within 30 min), simple (i.e., auto-analysis software), and cost-effective process (i.e., instrument-free) for cancer precision therapy.

Instrument-Free Detection of FXYD3 Using Vial-Based Immunosensor for Earlier and Faster Urothelial Carcinoma Diagnosis.

The incidence and 5 year recurrence rate of urothelial carcinomas (UCs), including UC of the bladder (UCB) and upper urinary tract UC (UTUC), have increased annually. There is a great need for a simple and fast point-of-care (POC) test for early diagnosis and amelioration in the survival rate. We present a POC test comprising a new vial-immunosensor, nanoenzyme, and iPhone 7 plus, which detects and quantifies the new biomarker FXYD domain-containing ion transport regulator 3 (FXYD3) in human urine for specific UC screening, tumor-grade classification, and postoperative monitoring by the grayscale value of the photograph taken. The performance of the proposed POC test was then verified using urine from 4 healthy people, 40 UCB patients (10 patients were low-grade and 30 patients were high-grade), and 13 UTUC patients (2 patients were low-grade and 11 patients were high-grade), confirming the accuracy and specificity by comparing the results with those obtained by enzyme-linked immunosorbent assay (ELISA). Moreover, we also designed a correction method that can make the grayscale values calculated by different smartphones close to the values calculated by iPhone 7 plus, resulting in the POC test enabling simple, fast, universal, and portable testing, data storage, and sharing for personal UCs screening and postoperative monitoring.

Combined Detection of CA19-9 and MUC1 Using a Colorimetric Immunosensor Based on Magnetic Gold Nanorods for Ultrasensitive Risk Assessment of Pancreatic Cancer.

We herein report a facile approach for developing an enzyme-free colorimetric immunosensor based on a magnetic iron oxide (IO)-coated gold nanorod (MGNR) nanocomposite with high electron transfer ability to accelerate the color bleaching reaction of methyl orange (MO) in the presence of NaBH4 for ultrasensitive detection of cancer antigens. In the case of MO, the reaction rate of MGNRs showed approximately 45.6-fold and 1520.8-fold higher than that of Cys-GNRs and NaBH4, respectively. The proposed colorimetric immunosensor was demonstrated to enable simple, cost-effective, sensitive, and specific carbohydrate antigen 19-9 (CA19-9) and mucin 1 (MUC1) detection for risk evaluation of pancreatic cancer (PC) with a small volume of serum sample without the use of any enhancing solutions or enzymes. By increasing the concentration of CA19-9 and MUC1, more MGNRs remained in the plate well to enhance the color bleaching of MO. As a proof-of-concept, the limit of detection (LOD) of 3.5 × 10-5 U/mL for CA19-9 and 5.2 × 10-6 U/mL for MUC1 was obtained with a wide linear quantification range from 8.6 × 10-5 U/mL to 1.4 × 10-2 U/mL for CA19-9 and 1.3 × 10-5 U/mL to 2.1 × 10-3 U/mL for MUC1, suggesting potential clinical applications for the early risk evaluation of PC.

A colorimetric immunosensor based on self-linkable dual-nanozyme for ultrasensitive bladder cancer diagnosis and prognosis monitoring.

We developed self-linkable Prussian blue (PB)-incorporated magnetic graphene oxide (PMGO) as a peroxidase-mimicking nanozyme with high oxidizability to 3,3',5,5'-tetramethylbenzidine (TMB), which generates significant absorption intensity for the colorimetric immunosensing of apolipoprotein A1 (ApoA1) in early bladder cancer (BC) diagnosis and prognosis monitoring. The ultrasensitive immunosensor was constructed using an ApoA1 antibody (AbApoA1)-functionalized chip (biochipApoA1) and self-linkable peroxidase-mimicking, PB-incorporated magnetic graphene oxide (PMGO). After incubating the sample and capturing ApoA1 proteins captured on the biochipApoA1, the PMGO was functionalized with AbApoA1, and then mouse IgG (PMGO-1), rabbit anti-mouse IgG antibody (PMGO-2), and goat anti-rabbit IgG antibody (PMGO-3) were added together. We envisioned that each captured ApoA1 protein would allow the retention of a large amount of PMGO through a self-linking process to amplify the colorimetric signal of TMB in the presence of H2O2. The linear detection range could be obviously widened in the presence of self-linkable PMGO-from 0.05 ng/mL to 100 ng/mL-compared with the group without signal amplification (from 1 ng/mL to 100 ng/mL). Our immunosensor analysis of ApoA1 in the urine of BC patients and healthy individuals was highly correlated with enzyme-linked immunosorbent assay measurements; moreover, the ApoA1 concentrations of patients with high-grade BC were significantly higher than those of patients with low-grade BC. After standard clinical treatment, a significant drop of ApoA1 concentration occurred in urine that was lower than the cut-off concentration, suggesting potential clinical applications of the new self-linkable PMGO-generating colorimetric immunosensor in early BC diagnosis and prognosis monitoring.

Aptasensor designed via the stochastic tunneling-basin hopping method for biosensing of vascular endothelial growth factor.

The Systematic Evolution Ligands by Exponential Enrichment (SELEX) is common used for selection of high affinity single-stranded DNA (ssDNA) aptamer with target protein. However, we do not know what the most stable configuration of the selected aptamer bound with target protein is. Therefore, a systematic search process using the stochastic tunneling-basin hopping (STUN-BH) method is proposed to find the most stable configuration of the ssDNA aptamer specific for vascular endothelial growth factor (VEGF) capture (AptVEGF; 5'-TGTGGGGGTGGACGGGCCGGGTAGA-3'). After the most stable configuration was obtained by the STUN-BH method, molecular dynamics (MD) simulation was carried out to investigate the thermal stability of AptVEGF/VEGF at 300 K in both vacuum and water. All molecular simulations were conducted with the large-scale atomic/molecular massively parallel simulator (LAMMPS), and the AMBER99SB force field was used to describe the atomic interactions for the current AptVEGF/VEGF system. The three most stable AptVEGF/VEGF configurations obtained by the STUN-BH method indicated that AptVEGF residues exhibit greater affinity for VEGF surface loop fragments as compared with surface alpha helix and beta sheet fragments. Results indicated that after the first AptVEGF (AptVEGF I) occupies most of the VEGF loop fragment, the second AptVEGF (AptVEGF II) is adsorbed by the rest of the VEGF loop fragment and the VEGF Chain B beta sheet fragment, resulting in a 24.8% reduction in binding strength as compared to that of AptVEGF I. Furthermore, when AptVEGF I and AptVEGF II chains were stably adsorbed by VEGF, the third AptVEGF (AptVEGF III) chain can only partially attach to VEGF, as confirmed by real AptVEGF-VEGF binding experiments. Lastly, we demonstrated that the aptasensor constructed according to MD simulation is highly sensitive for VEGF with a linear detection range of 10 pg/mL-10 ng/mL.

Genetic alterations of HER genes in chromophobe renal cell carcinoma.

Chromophobe (ch) renal cell carcinoma (RCC) is the 3rd most common subtype of RCC and occurs in 5% of all RCCs. Although chRCC generally demonstrates more favorable outcomes compared with other subtypes of RCC, there is a 6-7% probability of tumor progression and metastasis in this disease. The subclassification of a more aggressive subtype of chRCC may be useful for the management of this cancer. The Erb-B2 receptor tyrosine kinase 2 [also known as human epidermal growth factor receptor (HER) 2] gene has been reported to be important in chRCC. The present study aimed to further investigate the abnormalities of the HER family genes and their potential association with chRCC. Fluorescence in situ hybridization was performed on 11 chRCC tissue specimens, and the Spearman's rank correlation coefficient analysis was used to assess the results. The loss of one copy of the HER2 and HER4 genes was observed to be the major alteration of the tumor cells in all chRCC cases. Statistical data indicated that loss of the HER2 gene was strongly correlated with loss of the HER4 gene (P=0.019). The findings of previous studies were also combined for analysis, and were consistent with those of the present study. In addition, the amplification of HER1 was also strongly correlated with the amplification of HER4 (P=0.004). Furthermore, a high percentage of genetic structural rearrangements was observed in HER3 genes, which was significantly associated with amplification of HER2 (P=0.005). Certain alterations in the HER gene family were also noted as a phenomenom in chRCC. Therefore, the characterization of the underlying aberrant functions of HER genes may be of interest for additional studies in the context of using HER genes to distinguish between RCC subtypes in order to establish improved treatment guidelines.

A simple procedure for preparation of N-thiazol, thiadiazol, pyridyl and sulfanylamidocantharidinimines analogues and evaluation of their cytotoxicities against human HL-60, MCF7, Neuro-2a and A549 carcinoma cell.

The lab made an effort to prepare some biological active cantharidinimines by heating the reactant 1 and 2a-g, 5h-i and 7j-r amines to suitable temperature with ethanol to provide 18 N-thiazolyl-, sulfanyl-, aminopyridyl-, bromopyridyl-, alkylpyridyl- and hydroxypyridylcantharidinimines 3a-g, 4a-c, 6h-i and 8j-r in yield of 4-77% (Chart 1). These cantharidinimine derivatives were tested for their capabilities to suppress growth of the human carcinoma cell lines, HL-60, MCF7, Neuro-2a and A549, because the incidence rate is more prominent in Asian countries than western countries. Compounds 3c-d and 6h-i were found to have some antitumor activity in HL-60 but less activity in MCF cell and compounds 8j-l displayed some inhibition effects to A549 cell line, but less effect to Neuro-2a cell line. Compounds 8m-r had no cytotoxic effect against both cell lines. The cytotoxic effects of these cantharidinimine compounds seemed to be better than the cantharidinimide compounds which we had mentioned several years ago.

Characterization of a novel rat cholangiocarcinoma cell culture model-CGCCA.

AIM: To characterize a culture model of rat CCA cells, which were derived from a transplantable TTA-induced CCA and designated as Chang Gung CCA (CGCCA). METHODS: The CGCCA cells were cultured at in vitro passage 12 times on a culture dish in DMEM medium. To measure the doubling time, 10(3) cells were plated in a 96-well plate containing the growth medium. The cells were harvested 4 to 10 d after seeding, and a standard MTT assay was used to measure the growth. The phenotype of CACCA cell and xenograft was determined by immunohistochemical study. We also determine the chromosomal alterations of CGCCA, G-banding and spectral karyotyping studies were performed. The CGCCA cell line was transplanted into the nude mice for examining its tumorigenicity. 2-Deoxy-2-((18)F)fluoro-D-glucose (FDG) autoradiography was also performed to evaluate the FDG uptake of the tumor xenograft. RESULTS: The doubling time for the CGCCA cell line was 32 h. After transplantation into nude mice, FDG autoradiography showed that the tumors formed at the cell transplantation site had a latency period of 4-6 wk with high FDG uptake excluding necrosis tissue. Moreover, immunohistochemical staining revealed prominent cytoplasmic expression of c-erb-B2, CK19, c-Met, COX-II, EGFR, MUC4, and a negative expression of K-ras. All data confirmed the phenotypic features of the CGCCA cell line coincide with the xenograft mice tumors, indicating cells containing the tumorigenicity of CCA originated from CCA. In addition, karyotypic banding analysis showed that the diploid (2n) cell status combines with ring and giant rod marker chromosomes in these clones; either both types simultaneously appeared or only one type of marker chromosome in a pair appeared in a cell. The major materials contained in the marker chromosome were primarily identified from chromosome 4. CONCLUSION: The current CGCCA cell line may be used as a non-K-ras effect CCA model and to obtain information and reveal novel pathways for CCA. Further applications regarding tumor markers or therapeutic targeting of CCA should be addressed accordingly.

Comparison of auditory evoked potential index and clinical signs as indicator for laryngeal mask airway insertion.

OBJECTIVE: Auditory evoked potential (AEP) index is one of the several physiological parameters for assessing the depth of anesthesia. The purpose of this study was to investigate whether the AEP monitoring could provide a better information for assessment of anesthesia level in classic laryngeal mask airway (C-LMA) insertion than the use of clinical signs in general anesthesia with single standard dose of intravenous propofol and fentanyl. METHODS: One hundred and seventy adult patients requiring general anesthesia for minor surgery were recruited and randomized to receive AEP monitoring (group A) or judgment of clinical signs (group B) for assessment of anesthesia depth and optimal condition to insert the C-LMA. The insertion conditions, including jaw relaxation, movements, presence of airway trauma and airway reflex, successful insertion rate and induction time were recorded and compared. RESULTS: The two groups were demographically similar. In group A, baseline heart rate was slower than group B (74 ± 14 vs. 78 ± 14 beats/min, p = 0.0267) and persisted throughout the whole study period. There was no significant difference in the change of heart rate during induction of general anesthesia between both groups. The incidence of movement was reduced in group A patients with AEP monitoring in comparison with group B patients (2.4% vs. 28.2%, p < 0.0001); of the unwanted events, swallowing was 0% versus 7.1%, p = 0.0126; laryngospasm was 0% versus 4.7%, p  = 0.0430 and emergence of airway reflex was 1.2% versus 11.8%, p = 0.0050; the successful insertion rate was 100% versus 94.1%, p = 0.0232; and jaw relaxation was 83.5% versus 70.6%, p = 0.0448. There were no differences between both groups in trauma and induction time. CONCLUSION: This study demonstrated that AEP index provided better information for C-LMA insertion with higher successful rate, less emergence of airway reflex and lower incidence of movement during induction of general anesthesia with single dose of intravenous propofol and fentanyl.

Serial changes of pulse wave velocity and correlations with hemodynamic parameters during general anesthesia.

BACKGROUND: Increased pulse wave velocity (PWV) is a marker of increased arterial stiffness and is correlated with cardiovascular mortality and mortality of all causes in the elderly and in patients with essential hypertension and type 2 diabetes. There is also a positive correlation between PWV and arterial blood pressure. The changes of PWV in response to general anesthesia and surgical stimulation remain unclear. The aim of this study was to continuously monitor the PWV, blood pressure and heart rate, and to assess their correlations during general anesthesia in women receiving gynecologic surgery. METHODS: The values of PWV were obtained from calculation of the finger-to-toe distance divided by the transit time using dual-channel photoplethysmography system. The values of PWV, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were recorded before anesthesia induction, 5 min before incision, at incision, in continuation for at least 30 min thereafter, and 5 min after discontinuation of sevoflurane. The correlations between PWV and SBP, DBP and heart rate during the general anesthesia were analyzed using Pearson's correlation test. RESULTS: The serial records of PWV and hemodynamic parameters showed that PWV, SBP, DBP, and heart rate decreased after induction of anesthesia. SBP and DBP increased after surgical incision. There was a trend of progressively declining of PWV and DBP during the general anesthesia but SBP and heart rate remained stationary. All the values of PWV, SBP, DBP, and heart rate increased after discontinuation of anesthesia. There were significant correlations between PWV and SBP (r = 0.4558, P < 0.0001), between PWV and DBP (r = 0.2719, P < 0.0001), between PWV and pulse pressure (r = 0.2067, P < 0.0001), and between PWV and mean arterial pressure (r = 0.3969, P < 0.0001). CONCLUSIONS: We could evaluate the serial changes of PWV in response to general anesthesia and surgical stimulation using a simple and noninvasive dual-channel photoplethysmography system. The value of PWV, an index of arterial stiffness, has significant correlation with arterial blood pressure.