The in vitro metabolism of GMDTC in liver microsomes of human, monkey, dog, rat and mouse: Metabolic stability assessment, metabolite identification and interspecies comparison.

Sodium (S)- 2-(dithiocarboxylato((2 S,3 R,4 R,5 R)- 2,3,4,5,6-pentahydroxyhexyl)amino)- 4(methylthio)butanoate (GMDTC) is a compound that removes cadmium from kidney cells. This study aims to investigate the metabolic stability and metabolite identification of GMDTC in various liver microsomes, including those from human, monkey, dog, rat and mouse. The results show that the T1/2 values of GMDTC in human, monkey, dog, rat and mouse liver microsomes were 16.54, 18.14, 16.58, 15.16 and 16.00 min, respectively. While the hepatic extraction ratios (ERh) of GMDTC measured after 60 min incubation in these liver microsomes were 0.82, 0.70, 0.80, 0.75 and 0.79, respectively, indicating that GMDTC exhibits rapid hepatic metabolism and high hepatic clearance with no significant interspecies differences. Subsequent metabolite identification by high-resolution mass spectrometry revealed the presence of three metabolites, designated M1∼M3. The major metabolite products of GMDTC were found to be M1 and M2. The relative abundances of the hydrolysis products (M1 and M2) in human, monkey, dog, rat and mouse liver microsomes were found to be 97.18%, 97.99%, 95.94%, 96.31% and 93.43%, respectively, indicating that hydrolysis is the primary metabolic pathway of GMDTC in liver microsomes in vitro, and with no significant interspecies differences.

A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group.

BACKGROUND: This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016. METHODS: A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used. RESULTS: The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%. CONCLUSIONS: The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.

Establishment of LC-MS/MS Method for Determination of GMDTC in Rat Plasma and Its Application in Preclinical Pharmacokinetics.

Sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4(methylthio)butanoate (GMDTC) is the first compound to use cadmium repellent as an indication. In this paper, we established and validated a bioanalytical method for the determination of GMDTC in rat plasma, and used it to determine the drug concentrations in the plasma of rats after intravenous dosing in different genders and dosages. After pretreating the plasma samples with an acetonitrile-water-ammonia solution (70:30:1.25, v/v/v), liquid chromatographic separations were efficiently achieved with a XBridge C18 column using a 5 min gradient system of aqueous ammonium bicarbonate and 95% acetonitrile-water solution (95:5, v/v) as the eluent. The GMDTC and metolazone (internal standard, IS) detection were carried out using high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS), monitored at m/z 390.06-324.1 (for the GMDTC, tR: 2.03 min) and m/z 366.0-259.2 (for IS, tR: 3.88 min). The GMDTC was stable under various testing conditions, and this analytical method conforms to the verification standard of biological analysis methods. The half-life (t1/2) was determined to be 0.54-0.65 h for the intravenous, mean distribution volume and clearances were 1.08-2.08 L/kg and 1-3 L/h/kg, respectively. The AUC0-t and AUC0-∞ found after increasing the dosage exhibited a linear relationship with the administered dose. There were no statistically significant differences in the values obtained for the different genders at dosages of 50, 100 and 250 mg/kg, respectively (p > 0.05). This is the first report of a bioanalytical method to quantify GMDTC in rat plasma using LC-MS/MS, which provides useful information for the study of its pharmacological effects and clinical applications.

CD133 expression and MYCN amplification induce chemoresistance and reduce average survival time in pediatric neuroblastoma.

Objectives Neuroblastoma (NB) is the most common pediatric solid tumor derived from the sympathetic nervous system. MYCN is amplified in nearly half of patients with NB, and its association with rapid disease progression and poor outcome is controversial. Characterization of cancer stem cells (CSCs) in NBs has been rarely studied. This study was performed to determine whether MYCN and CD133+ CSCs are associated with chemotherapy resistance and the survival time of patients with NB. Methods Fifty patients with an unequivocal pathological diagnosis of NB were recruited. MYCN expression levels were measured before therapy. CSCs were derived and their multipotency tested by directed differentiation. The patients' responses to chemotherapy and average survival time were compared among the groups as follows: CD133+, CD133-, MYCN amplification ≥5 times (i.e. MYCN≥5), MYCN<5, CD133+ plus MYCN≥5, and CD133- plus MYCN<5. Results CD133+ CSCs differentiated into neuron-like cells. CD133+ patients had a significantly poorer response to chemotherapy than did CD133- patients. CD133+ plus MYCN≥5 patients had a significantly shorter average survival time than did CD133- plus MYCN<5 patients. Conclusions CD133+ CSCs are chemoresistance. CD133 expression and MYCN amplification can be used together as a prognostic indicator of disease outcome.

Effects of small-dose dexmedetomidine on hyperdynamic responses to electroconvulsive therapy.

BACKGROUND: Acute hemodynamic responses to electroconvulsive therapy (ECT) may increase the risk of cardiovascular complications in vulnerable patients. The aim of the current study was to assess the effect of small-dose dexmedetomidine on hyperdynamic responses to ECT. METHODS: Seventy-eight patients were enrolled and randomly allocated to receive either 0.2 µg/kg dexmedetomidine (Dex group, n = 39) or saline (Control group, n = 39) prior to ECT. Heart rate (HR) and mean arterial pressure (MAP) were recorded immediately after the administration of dexmedetomidine (T1), and 0, 1, 3, 5 and 10 min after the electrical stimuli ended (T2, T3, T4, T5 and T6). In addition, the peak HR after ECT, seizure duration, recovery time, and incidence rates of post-ECT adverse effects (agitation, headache and nausea) were also recorded. RESULTS: HR and MAP in the Dex group were significantly lower than those in the Control group from T2 to T5. In addition, peak HR was significantly lower in the Dex group compared with that in the Control group. Seizure length and time to spontaneous breathing, eye opening, and obeying commands in the Dex group were similar to those in the Control group. The incidence rates of post-ECT agitation and headache in the Dex group were significantly lower than that in the Control group. CONCLUSION: The administration of 0.2 µg/kg dexmedetomidine to patients receiving ECT leads to a significant reduction in HR, MAP, and peak HR responses to ECT without altering seizure duration or delaying recovery. Furthermore, dexmedetomidine effectively reduced the incidence rates of post-ECT adverse effects such as agitation and headache.

Dexmedetomidine Combined With Intravenous Anesthetics in Electroconvulsive Therapy: A Meta-analysis and Systematic Review.

OBJECTIVE: The aim of this study was to investigate how the combined use of dexmedetomidine with intravenous anesthetics influences seizure duration and circulatory dynamics in electroconvulsive therapy (ECT). METHODS: A literature search was performed to identify studies that evaluated the effect of dexmedetomidine on motor- or electroencephalogram (EEG)-based seizure durations and maximum mean arterial pressure (MAP) and heart rate (HR) after ECT. Moreover, recovery time and post-ECT agitation were evaluated. RESULTS: Six studies enrolling 166 patients in 706 ECT sessions were included. There was no significant difference in motor or EEG seizure duration between dexmedetomidine and nondexmedetomidine groups [motor: 6 studies; mean difference (MD), 1.62; 95% confidence interval (CI), -2.24 to 5.49; P = 0.41; EEG: 3 studies; MD, 2.34; 95% CI, -6.03 to 10.71; P = 0.58]. Both maximum MAP and HR after ECT were significantly reduced in the dexmedetomidine group (MAP: 6 studies; MD, -4.83; 95% CI, -8.43 to -1.22; P = 0.009; HR: 6 studies; MD, -6.68; 95% CI, -10.74 to -2.62; P = 0.001). Moreover, the addition of dexmedetomidine did not significantly prolong recovery time when the reduced-dose propofol was used (4 studies; MD, 63.27; 95% CI, -15.41 to 141.96; P = 0.12). CONCLUSIONS: The use of dexmedetomidine in ECT did not interfere with motor and EEG seizure durations but could reduce maximum MAP and HR after ECT. Besides, the addition of dexmedetomidine in ECT did not prolong recovery time when reduced-dose propofol was used. It might be worthwhile for patients to receive dexmedetomidine before the induction of anesthesia in ECT.

[Effects of shangke jiegu tablet on the gene expressions of osteoprotegerin and osteoprotegerin ligand in the repairing process of mandibular defect rabbits].

OBJECTIVE: To explore the mechanism of Shangke Jiegu Tablet (SJT)in repairing the mandibular defect. METHODS: Totally 72 healthy male New Zealand rabbits were randomly divided into the normal control group (n = 24), the model group (n = 24), and the SJT group (n = 24). Then the mandibular defect model was established. Animals in the normal control group and the model group were fed with normal forage, while those in the SJT group were fed with SJT forage. On the day 7, 14, 28, and 56 after model establishment, 6 rabbits were killed in each group. The bone was collected from the mandibular defect. The gene expressions of osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL) were detected by means of RT-PCR. The positive dyeing strength and area of the bone tissue were detected by means of immunohistochemical technique. RESULTS: Compared with the normal control group, the degree of OPGmRNA expression was remarkably up-regulated on day 7 after model establishment (P < 0.05) and the degree of OPGLmRNA expression was remarkably up-regulated on day 14 after model establishment (P < 0.05) in the model group. Compared with the model group, the degree of OPGmRNA expression was remarkably up-regulated (P < 0.05), and the positive dyeing strength and area of bone tissue were stronger and broader on day 14, 28, and 56 after model establishment in the SJT group. The degree of OPGLmRNA expression was remarkably down-regulated (P < 0.05), and the positive dyeing strength and area of bone tissue were weaker and smaller on day 14 after model establishment in the SJT group. The ratio of OPGmRNA/OPGLmRNA was remarkably up-regulated on day 14, 28, and 56 after model establishment (P < 0.05). CONCLUSION: The effect mechanism of promoting mandibular defect repairing by SJT may be correlated to regulating the expressions of OPGmRNA and OPGLmRNA.

[The role of PD-ECGF and VEGF in proliferative and involuted mechanism of the infantile capillary hemangiomas].

OBJECTIVE: To explore the relation between the expressions of PD-ECGF and VEGF and the evolution of capillary hemangioma, so as to provide theoretical basis for treatment. METHODS: Fourty cases with capillary hemangioma, proved by pathologic method, were randomly selected and divided into proliferative (n=22) and involuted groups (n=18), according to the Mulliken standard. 8 specimens from 8 children with prepuce operation were used as control group. All the specimens were fixed, embedded and underwent HE staining. The expression of PD-ECGF, VEGF and CD34 in endothelial cells were detected by immunohistochemistry. The microvessel-density (MVD) was also calculated. The results were analyzed by SPSS12.0. RESULTS: The positive expression rates of PD-ECGF and VEGF were 95.45% (21/22) and 86.36% (19/22) in proliferative hemangioma, 77.78% (14/18) and 66.67% (12/ 18) in involuted hemangioma, 37.50% (3/8) and 37.50% (3/8) in normal skin. MVD in proliferative and involuted hemangioma and normal skin was 93.68 +/- 20.56, 51.94 +/- 20.73 and 17.50 +/- 5.30, respectively. There was a significant difference in PD-ECGF expression and MVD between the proliferative and involuted groups, or between the hemangioma and control groups (P < 0.05). The VEGF was significantly different between the proliferative and involuted groups, or between the proliferative and control groups (P < 0.05), but not between the involuted and control groups (P > 0.05). The expression of VEGF, PD-ECGD and MVD showed a positive relationship. CONCLUSIONS: PD-ECGF and VEGF have a synergetic effect in the proliferation of micro-vessels. PD-ECGF may enhance the activity of thymidine phosphorylase. They play an important role in the proliferation and involution of hemangioma.

Laparoscopic splenectomy: color Doppler flow imaging for preoperative evaluation.

BACKGROUND: Laparoscopic splenectomy (LS) is currently the standard approach for resection of a normal-sized spleen. However, this method becomes technical challenge in cases of splenomegaly due to intraoperative hemorrhage. A complete understanding of the splenic vessel anatomy is important to facilitate the difficult laparoscopic procedure. In this retrospective study, we examined the role of color Doppler flow imaging (CDFI) in splenic vessel anatomy and evaluated its value for LS. METHODS: Forty-eight patients who underwent splenectomy for various hematologic and autoimmune disorders from May 2004 to December 2007 were enrolled in this study. Twenty-three patients underwent preoperative CDFI examination that included examination of the anatomic type of splenic pedicle, the adjacent relationship between the splenic vessel and pancreas, and spleen size (CDFI group). In the remaining 25 patients, ultrasonic inspections of the splenic vessel were not performed (non-CDFI group). Laparoscopic splenectomies in the CDFI group were performed in accordance with the information provided by the preoperative CDFI in each patient. In the non-CDFI group, LS was performed according to the conventional method. In the CDFI group, the constituent ratios of the above-mentioned parameters by CDFI were compared with those recorded during LS using the chi square test. The effectiveness of the technique on surgery in both groups was compared with an independent sample Student's t test. RESULTS: All laparoscopic splenectomies in both groups were performed successfully. However, 2 cases in the non-CDFI group were converted to LS with the assistance of micro-incision because the branches of the splenic vein were inadvertently torn. Two anatomic types of splenic pedicle and four different adjacent relationships between the splenic vessel and pancreas were detected by CDFI. About 80% of spleens fit the criteria of megalosplenia. There were no statistically significant differences between the constituent ratios of the parameters by CDFI and those by intraoperative telerecording in the CDFI group (chi(2) = 0.383, 1.072, 0.119, P = 0.536, 0.784, 0.730). However, statistically significant differences were observed in the operative time ((158.70 +/- 42.51) minutes vs (200.65 +/- 47.89) minutes, P = 0.003), intraoperative blood loss ((55.87 +/- 17.36) ml vs (101.83 +/- 62.21) ml, P = 0.001), and recovery time of gastrointestinal function ((24.39 +/- 8.88) hours vs (30.60 +/- 9.45) hours, P = 0.024) between the groups. CONCLUSIONS: The individual operative route and schedule can be successfully determined on the basis of various kinds of reproducible anatomic frameworks of the spleen provided by preoperative CDFI. This technique facilitates the surgical procedure, shortens the operative time, reduces intraoperative blood loss and decreases the risk of LS in splenomegaly cases.

Thermo-magnetic recording on a Co/Pt perpendicular film by a sharp metallic probe.

We studied a method of heat-assisted magnetic recording (HAMR). The recording medium is a strongly coupled Co/Pt multilayered thin film, suitable for perpendicular recording. Field emission current from a scanning tunneling microscope (STM) tip is used as the heating source. Pulse voltages of 5 V were applied to the film. Experimental results show that an average mark size of 100-120 nm was achieved, with the minimum being 45 nm. Models of domain stability and dynamic domain formation are built to quantitatively explain the experimental results. They agree well with experiments. The models give us future directions for achieving small marks for ultra-high recording density.