Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the mod-ulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theo-retically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(p-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electro-phoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while pre-senting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

BACKGROUND: Patients with atrial fibrillation (AF) and prior stroke history have a high risk of cardiovascular events despite anticoagulation therapy. It is unclear whether catheter ablation (CA) has further benefits in these patients. METHODS: AF patients with a previous history of stroke or systemic embolism (SE) from the prospective Chinese Atrial Fibrillation Registry study between August 2011 and December 2020 were included in the analysis. Patients were matched in a 1:1 ratio to CA or medical treatment (MT) based on propensity score. The primary outcome was a composite of all-cause death or ischemic stroke (IS)/SE. RESULTS: During a total of 4.1 ± 2.3 years of follow-up, the primary outcome occurred in 111 patients in the CA group (3.3 per 100 person-years) and in 229 patients in the MT group (5.7 per 100 person-years). The CA group had a lower risk of the primary outcome compared to the MT group [hazard ratio (HR) = 0.59, 95% CI: 0.47-0.74, P < 0.001]. There was a significant decreasing risk of all-cause mortality (HR = 0.43, 95% CI: 0.31-0.61, P < 0.001), IS/SE (HR = 0.73, 95% CI: 0.54-0.97, P = 0.033), cardiovascular mortality (HR = 0.32, 95% CI: 0.19-0.54, P < 0.001) and AF recurrence (HR = 0.33, 95% CI: 0.30-0.37, P < 0.001) in the CA group compared to that in the MT group. Sensitivity analysis generated consistent results when adjusting for time-dependent usage of anticoagulants. CONCLUSIONS In AF patients with a prior stroke history, CA was associated with a lower combined risk of all-cause death or IS/SE. Further clinical trials are warranted to confirm the benefits of CA in these patients.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC₅₀ = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC₅₀ = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

OBJECTIVE: To assess the value of fluorescence in situ hybridization (FISH) technique for the verification of the clonalities of non-clonal cytogenetic abnormalities (n-CCA) identified by conventional chromosome banding analysis (CBA) in patients with Myelodysplastic syndrome (MDS). METHODS: Clinical data and results of karyotyping and FISH assays for 91 patients of MDS with n-CCA identified by CBA were retrospectively analyzed. In total 94 non-clonal +8, 5q-, -7/7q- or 20q- were detected by CBA, among which 43 (45.7%) were verified to be clonal abnormalities by FISH. RESULTS: The detection rates for +8, 5q-, -7/7q- and 20q- by FISH were 47.6% (30/63), 25% (2/8), 41.7% (5/12), 40% (2/5) and 66.7% (4/6), respectively, with the positive cells accounting for 4% to 90% of all counted cells, with a median value of 7%. The 91 patients were divided into three groups including ≥ 20, 10 ~< 20 and < 10 based on the numbers of metaphase cells in CBA, and the detection rates by FISH for the three groups were 43.7% (31/71), 33.3% (3/9) and 63.6% (7/11), respectively, which showed no statistically difference (P > 0.05). Continuous CBA and FISH surveys were conducted for 26 patients who received supportive treatment, and the results revealed that 91.7% (11/12) of FISH-verified positive abnormalities had persisted, whereas 92.9% (13/14) of the n-CCA verified as negative by FISH was transient. CONCLUSION Nearly half of the CBA identified n-CCA have been verified as clonal aberrations by FISH, and the FISH detection rate showed no correlation with the number of metaphase cells. FISH test is strongly recommended for verifying the clonalities of n-CCA detected by CBA, and continuous cytogenetic survey of the patients with MDS is necessary.
Humans ; In Situ Hybridization, Fluorescence ; Retrospective Studies ; Chromosome Aberrations ; Karyotyping ; Myelodysplastic Syndromes/genetics*

Selective dorsal neurotomy (SDN) is a surgical treatment for primary premature ejaculation (PE), but there is still no standard surgical procedure for selecting the branches of the dorsal penile nerves to be removed. We performed this study to explore the value of intraoperative neurophysiological monitoring (IONM) of the penile sensory-evoked potential (PSEP) for standard surgical procedures in SDN. One hundred and twenty primary PE patients undergoing SDN were selected as the PE group and 120 non-PE patients were selected as the normal group. The PSEP was monitored and compared between the two groups under both natural and general anesthesia (GA) states. In addition, patients in the PE group were randomly divided into the IONM group and the non-IONM group. During SDN surgery, PSEP parameters of the IONM group were recorded and analyzed. The differences in PE-related outcome measurements between the perioperative period and 3 months' postoperation were compared for the PE patients, and the differences in effectiveness and complications between the IONM group and the non-IONM group were compared. The results showed that the average latency of the PSEP in the PE group was shorter than that in the normal group under both natural and GA states (P < 0.001). Three months after surgery, the significant effective rates in the IONM and non-IONM groups were 63.6% and 34.0%, respectively (P < 0.01), and the difference in complications between the two groups was significant (P < 0.05). IONM might be useful in improving the short-term therapeutic effectiveness and reducing the complications of SDN.
Male ; Humans ; Premature Ejaculation/surgery* ; Intraoperative Neurophysiological Monitoring/methods* ; Prospective Studies ; Neurosurgical Procedures/methods* ; Penis/surgery* ; Retrospective Studies

Between August and September, 2021, this study included 605 SARS-CoV-2 natural infection cases and 589 SARS-CoV-2 breakthrough cases from Nanjing and Yangzhou, as well as 690 inactivated COVID-19 vaccine recipients from Changzhou, China. In SARS-CoV-2 natural infection cases, the age range was 19-91 years (median age: 66 year), and the medians(Q₁,Q₃) of IgG titers were 0.19 (0.06-1.31), 3.70 (0.76-69.48), 15.31 (2.59-82.16), 4.41 (0.99-31.74), 2.31 (0.75-13.83), 2.28 (0.68-9.94) and 2.80 (1.00-9.53) at one to seven weeks after SARS-CoV-2 infection, respectively. In SARS-CoV-2 breakthrough cases, the age range was 18-76 years (median age: 45 year), and the medians(Q₁,Q₃)of IgG titers were 1.93 (0.34-26.67), 38.87 (7.90-121.0), 75.09 (11.85-123.70), 21.97 (5.20-95.58), 13.97 (3.47-46.82), 9.56 (2.48-33.38) and 4.38 (1.87-11.00) at one to seven weeks after SARS-CoV-2 infection, respectively. In inactivated COVID-19 vaccine recipients, the age range was 18-87 years (median age: 47 years), and the medians(Q₁,Q₃)of IgG titers were 16.22 (15.84-33.42), 5.35 (2.96-13.23), 3.30 (2.18-6.18), 3.14 (1.16-5.70), 2.77 (1.50-4.52), 2.72 (1.76-4.36), 2.01 (1.27-3.51) and 1.94 (1.35-3.09) at one to eight months after SARS-CoV-2 infection, respectively. The results suggested that IgG antibodies increased gradually within two weeks after SARS-CoV-2 infection, then declined gradually at three to seven weeks in SARS-CoV-2 natural infection cases. In SARS-CoV-2 breakthrough cases, IgG antibodies increased rapidly within two weeks, then declined gradually at three to seven weeks after SARS-CoV-2 infection. Additionally, IgG antibodies decreased rapidly within three months, then decreased gradually and remained at a low level within three months after immunization.
Humans ; Aged ; Middle Aged ; Young Adult ; Adult ; Aged, 80 and over ; Adolescent ; COVID-19 Vaccines ; COVID-19 ; SARS-CoV-2 ; Kinetics ; Antibodies, Viral ; Immunoglobulin G

OBJECTIVE: To study and compare the effect of indwelling drainage tube and extubation time on occult hemorrhage and functional recovery after total hip arthroplasty(THA). METHODS: From July 2017 to June 2018, 123 patients who underwent THA in our hospital for the first time were selected as the subjects of study. According to whether the drainage tube was retained or not and the time of extubation, they were divided into three groups:in group A, 41 patients (24 males, 17 females, age 53 to 77 years) did not put drainage tube after THA;in group B, 41 patients were removed 24 hours after THA, 26 males and 15 females, aged 55 to 74 years;in group C, 41 patients were removed 48 hours after THA, 25 males and 16 females, aged 52 to 75 years. The VAS score of pain 72 hours after THA, the total and recessive blood loss, the time of starting functional exercise, and the incidence of postoperative limb swelling were recorded. All the patients were followed up for one year after discharge. Harris hip score was used to evaluate the degree of hip function recovery one year after operation. RESULTS: The occult blood loss of group A, B and C were(513.6±25.3), (521.7±33.4), (519.3±29.8) ml, respectively, with no significant difference(>0.05). There was no significant difference in blood loss in operation among the three groups(>0.05). In group B and C, the postoperative apparent blood loss was more than that in group A (<0.05). There was no significant difference in VAS scores of the three groups before and 72 hours after operation (>0.05). The time of getting out of bed in group A was shorter than that in group B and C (<0.05), and that in group B was shorter than that in group C(<0.05). The Harris hip score at 1 year after operationof the three groups was significantly higher than that of before operation (<0.05). There was no significant difference in Harris hip score before and after operation among three groups (>0.05). There was no significant difference in the incidence of complications among three groups (>0.05). CONCLUSION Whether the drainage tube is left or not and the time of extubation have no significant effect on the latent blood loss and functional recovery after THA, but without drainage tube after THA can reduce the apparent blood loss, patients can get out of bed at 6 hours after THA, which is more conducive to the recovery and nursing of patients.
Aged ; Airway Extubation ; Arthroplasty, Replacement, Hip ; Drainage ; Female ; Humans ; Male ; Middle Aged ; Recovery of Function ; Treatment Outcome

Objective:To explore the reference ranges and influential factors of disturbance coefficient (DC) in children without craniocerebral injury at different ages.Methods:Two hundred children without craniocerebral injury admitted to the Department of Orthopaedics in Children′s Hospital of Chongqing Medical University from May 2018 to October 2019 were enrolled in this prospective study. The children were divided into four groups according to age, 0-1 year, >1-3 years, >3-5 years and >5-16 years, each of which included 50 children. Each child had DC measured twice with the non-invasive dynamic cerebral edema monitor, and the average value was used as the terminal DC value. Each measurement lasted 15 minutes, 12 hours apart. The difference of DC values among the four groups and between different genders were compared with ANOVA test and nonparametric test. And the Loess local weighted nonparametric regression analysis was used to explore the change of DC according to the increase of age, weight and head circumference (HC).Results:The reference values of DC for children of 0-1 year,>1-3 years, >3-5 years, and >5-16 years were 60±14, 92±18, 112±18, 135±18, respectively ( F=175.690, P<0.01). There was no statistical significance in DC between male and female children either in the whole or in each separate age group (103 (81, 125) vs. 102 (68, 123) , Z=-0.739, P=0.460; 59 (52, 68) vs. 57 (53, 65) , Z=-0.243, P=0.808; 88 (81, 105) vs. 95 (70, 105) , Z=-0.776, P=0.437; 117 (99, 120) vs. 113 (101, 123) , Z=-0.170, P=0.865; 137 (123, 143) vs. 142 (123, 160) , Z=-1.279, P=0.201). When the child′s age was younger than 5 years, weight was less than 18 kg or HC was less than 51 cm, the DC increased significantly with the increase of age, weight or HC. However, when the age, weight and HC were over the above values, the DC did not show obvious increase, but approaching to stable values of 135, 130, and 130, respectively. Conclusions:For children without craniocerebral injury, the reference values of DC are obviously different at different ages. DC is positively related to age, weight and HC, but not related to gender.

Objective: To investigate the incidence and related independent risk factors of depression in treatment-naïve Han ethnic Chinese patients with chronic hepatitis C. Methods: Nine hundred and ninety-seven Han Chinese patients with confirmed chronic HCV infection were enrolled. Beck’s depression inventory scale was used to assess depression score. Patients were divided into two groups according to the score: score≥17, depression group (16.85%, 168/997); score <17, no depression group (83.15%, 829/997). Multivariate logistic regression was used to analyze independent risk factors related with the onset of depression in patients with chronic hepatitis C. Results: There was a statistically significant difference between the two groups in terms of gender distribution, marital status, education level, income level and smoking status (P < 0.05). Independent risk factors were female [odds ratio (OR) = 3.85; 95% CI: 2.28-6.50, P = 0.001], decompensated cirrhosis [OR = 2.31; 95% CI: 1.20-4.48, P = 0.013], unmarried [OR = 2.01; 95% CI: 1.12-3.60, P = 0.019], separated [OR = 17.39; 95% CI: 1.64-184.47, P = 0.018], divorced [OR = 3.82; 95% CI: 1.36-10.74, P = 0.011], without higher education [OR = 2.04; 95% CI: 1.22-3.42, P = 0.007], low income [OR = 3.94; 95% CI: 1.38-11.28, P = 0.011], middle income [OR = 2.96; 95% CI: 1.02-8.62, P = 0.047], uninterrupted smoking [OR = 3.67; 95% CI: 2.13-6.31, P = 0.001], and previously smoked [OR = 3.33, 95% CI: 1.66-6.68, P = 0.001]. Conclusion The incidence of depression in patients with chronic hepatitis C is relatively high. The independent risk factors related with depression include female, unmarried, separated, and divorced, without higher education, low and middle-income level, smoking and disease progression to decompensated cirrhosis, but no significant correlation between hepatitis C virus genotypes and viral load.