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Objective:To evaluate the effect of intraoperative individualized systolic blood pressure (SBP) management on myocardial injury after hip replacement in elderly patients at high risks of hypertension.Methods:One hundred and eighty-two patients of either sex, aged 60-89 yr, with body mass index of 18-26 kg/m 2, with a history of hypertension requiring drug treatment and stratified high risk factors of cardiovascular risk factors, scheduled for elective hip replacement under general anesthesia, were divided into 2 groups ( n=91 each) using a random number table method: routine management group and individualized SBP management group. Individualized SBP management group maintained the intraoperative SBP at 90%-110% of the baseline value, and routine management group implemented blood pressure management according to the current routine clinical pathway.The intermedian cubital venous blood samples were collected before surgery and at 24, 48, and 72 h after surgery for determination of the serum concentrations of high sensitivity cardiac troponin T. Postoperative myocardial injury and myocardial infarction were also recorded. The 30-day all-cause mortality was recorded on day 30 after surgery. Results:The incidence of postoperative myocardial injury and serum concentrations of high sensitivity cardiac troponin T at 24, 48 and 72 h after surgery were significantly decreased, and the length of hospital stay was shortened in individualized SBP management group as compared with routine management group ( P<0.05). Conclusions:Intraoperative individualized SBP management can reduce the postoperative myocardial injury in elderly patients at high risk of hypertension undergoing hip replacement.
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Objective:To investigate the efficacy of liposomal doxorubicin intensive preconditioning regimen and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in treatment of leukemia.Methods:The data of 20 patients with intensive preconditioning regimen allo-HSCT who were admitted to Shenzhen Second People's Hospital from January 2016 to June 2017 were retrospectively analyzed. The transplantation effect, occurrence of complications and prognosis of patients were analyzed.Results:The median time of granulocyte engraftment was 17 d (13-23 d); the median time of platelet engraftment was 22.5 d (minimum 13 d, maximum >90 d). The acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 2 cases and 1 case, respectively. Eight cases occurred hemorrhagic cystitis, 15 cases occurred Epstein-Barr viremia, 8 cases occurred cytomegaloviremia, 1 case occurred sepsis, 1 case occurred acute liver injury, and 2 cases occurred fungal pneumonia. The median follow-up time was 31.7 months (0.8-53.8 months). One patient died of intracranial infection on the 25th day after transplantation; 3 patients relapsed during the follow-up period, and 2 of them died; the other 16 patients carried 100% donor genes during the follow-up period.Conclusions:The liposomal doxorubicin intensive preconditioning regimen and allo-HSCT have a good effect on leukemia. Increasing the intensity of pretreatment does not increase the treatment-related adverse reactions. The incidence rates of Epstein-Barr viremia and cytomegaloviremia are high, but they are improved after active treatment.
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The dorsal lingual epithelium, which is composed of taste buds and keratinocytes differentiated from K14+ basal cells, discriminates taste compounds and maintains the epithelial barrier. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotic cells. How METTL3-mediated m6A modification regulates K14+ basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear. Here we show knockout of Mettl3 in K14+ cells reduced the taste buds and enhanced keratinocytes. Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds. Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization, but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery. Mechanically, we revealed that the most frequent m6A modifications were enriched in Hippo and Wnt signaling, and specific peaks were observed near the stop codons of Lats1 and FZD7. Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.
Subject(s)
Animals , Mice , Epithelium/metabolism , Homeostasis , Methylation , Methyltransferases/metabolism , RNA , Taste Buds/metabolismABSTRACT
Objective:To evaluate the relationship between declined preoperative left ventricular diastolic function and postoperative increased extravascular lung water (EVLW) in the patients undergoing transurethral resection of the prostate (TURP).Methods:A total of 116 patients, aged 55-90 yr, of American Society of Anesthesiologists physical status Ⅰ-Ⅲ, with body mass index of ≤30 kg/m 2, undergoing elective TURP under general anesthesia, without increased EVLW before surgery, were included in the study.Lung ultrasound examination was performed and lung ultrasound scores were assessed before leaving PACU.Increased EVLW was defined as lung ultrasound score ≥20.The occurrence of increased EVLW after operation was recorded, and patients were divided into increased EVLW group and non-increased EVLW group according to whether increased EVLW occurred.Multivariate logistic regression analysis was used to identify the risk factors for postoperative increased EVLW. Results:The results of multivariate logistic regression analysis showed that declined preoperative left ventricular diastolic function was an independent risk factor for postoperative increased EVLW ( P<0.05). Conclusions:Declined preoperative left ventricular diastolic function is an independent risk factor for postoperative increased EVLW in the patients undergoing TURP.
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Objective To investigate the clinicopathological significance of PDC in liver metastases and analyze the correlation of PDC between liver metastases and primary lesions. Methods Retrospective analysis of 72 matched cases of colorectal cancer with liver metastases was performed. The PDC in primary tumor and liver metastatic lesion was interpreted synchronously, and then the relationship between PDC in liver metastasis and clinicopathological parameters was analyzed based on the correlation of PDC between primary and metastatic lesions. In addition, PDC were interpreted in accordance with Uenos' standard. Results Among the 72 cases of liver metastasis of colorectal cancer, the number of G1, G2, and G3 graded by PDC was 28, 24, and 20, respectively. The PDC in liver metastatic lesion was correlated with tumor budding in liver metastatic lesion and PDC grade of primary lesion. No significant correlation with the size and number of liver metastatic lesion, the site, WHO grade, depth of invasion, lymph node metastasis, vascular invasion or tumor budding of the primary lesion was observed. Conclusion A positive correlation is found between liver metastasis of colorectal adenocarcinoma and PDC grade of primary tumor. Evaluating the PDC grade of primary tumor may provide a reference for the risk of liver metastasis.
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Objective:To explore the efficacy and safety of in-class transition from proteasome inhibitor bortezomib to ixazomib in the treatment of newly-treated patients with multiple myeloma (MM).Methods:The clinical data of 63 newly-treated MM patients in Shenzhen Second People's Hospital from January 2018 to December 2020 were retrospectively analyzed. They were divided into transition group (23 cases) and bortezomib group (40 cases). Both groups were treated with bortezomib-containing regimen as the first-line treatment regimen. In case of intolerable adverse reactions, patients in the transition group were treated with ixazomib instead of bortezomib, while the patients in the bortezomib group did not undergo drug transition. The curative effect and progression-free survival (PFS) were compared between the two groups.Results:In the transition group, the overall response rate (ORR) before in-class transition was 95.7% (22/23), the rate of ≥ very good partial remission (VGPR) was 52.2% (12/23); the ORR after transition was 95.7% (22/23), and the rate of ≥ VGPR was 82.6% (19/23). In the bortezomib group, ORR was 90.0% (36/40), and the rate of ≥ VGPR was 72.5% (29/40). There was no significant difference in ORR and the rate of ≥VGPR between the two groups ( χ2 = 0.64, P=0.424; χ2 = 0.82, P = 0.364). The median number of cycles of PI therapy in the transition group was 9, and the median PFS time was not reached. The median number of cycles of PI therapy in the bortezomib group was 7.5, and the median PFS time was 30.0 months (95% CI 19.1-40.9 months), there was no significant difference in PFS between the two groups ( P = 0.275). In the bortezomib group, 12 patients discontinued bortezomib due to adverse reactions, the median PFS time was 20.0 months (95% CI 12.6-27.4 months), and the PFS of patients who discontinued PI in the transition group and the bortezomib group was compared, the difference was statistically significant ( P = 0.043). In the transition group, 21 patients (21/23, 91.3%) developed peripheral neuropathy, and the incidence of ≥grade 3 adverse reactions was 13.0% (3/23); in the bortezomib group, 22 patients (22/40, 55.0%) developed peripheral neuropathy, and the incidence of ≥grade 3 adverse reactions was 12.5% (5/40). Conclusions:For newly-treated MM patients, the transition from bortezomib to ixazomib can improve the depth of remission and reduce the recurrence caused by the discontinuation of PI.
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Objective Shkbp is also called Shkbp1,can competitively inhibit binding CIN85 and c-Cbl,thereby blocking the epidermal growth factor receptor (EGFR) endocytosis and degradation,to play a role in tumor promotion.This study aims to explore the changes in blood cell classification and T cell subsets in blood,bone marrow,and spleen in Shkbp1-deletion (Shkbp-1-/-) mice.Methods Shkbp-1-/-transgenic mice were identified by PCR genotyping.Blood cell classification was performed using an automatic classification system.Flow cytometry was used to detect the T lymphocyte subsets in the blood,bone marrow,and spleen of Shkbp-1-/-and control mice.Results Routine blood examination showed that neutrophils and eosinophils tended to increase and showing significant differences,and there was no significant difference in lymphocytes.The flow cytometry results showed that there was a decrease of CD4+CD8+ double positive cells and increase of bone marrow CD3+ and CD4+ cells in the control group.However,there was a decreasing trend of CD3+,CD4+,CD8+,and CD4+CD8+ cells in the spleen tissues.Conclusions Shkbp1 is involved in the maturation and differentiation of blood cells,and affects the number of immune cells.This study lays a foundation for the study of how Shkbp1 is involved in the differentiation of blood cells.
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Objective To observe the effect of early using butylphthalide injection before and after thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) on the clinical prognosis of patients with ultra-early acute cerebral infarction (ACI). Methods A prospective study was conducted, 81 patients with ACI admitted to the Department of Neurology of Tangshan Worker's Hospital from September 2014 to March 2016 were enrolled, and they were divided into a control group (40 cases) and an observation group (41 cases) according to the random number table. Both groups were given routine treatments, such as drugs for lowering blood pressure and blood sugar, decreasing blood lipid to stabilize plaque, neuroprotection, activating blood circulation and removing blood stasis, etc. On the basis of conventional treatment, the control group was directly treated with rt-PA intravenous (IV) thrombolytic therapy according to the guidelines of thrombolytic therapy; in the observation group, the patients immediately underwent CT head examination after admission to decide whether the thrombolytic therapy was necessary, if the therapy was decided to be done, during doctors waiting for the laboratory results or transferring patients, IV drip of butylphthalide sodium chloride 100 mL. After IV drip thrombolytic therapy, if the disease condition was stabilized, the head CT was re-examined to exclude intracranial hemorrhage, if no such hemorrhage, IV drip of butylphthalide sodium chloride 100 mL was continuously given, twice daily for consecutive 14 days with the interval between the two times of IV drip being 7 hours daily. When patient's condition was changed, the re-examination of head CT could be done at any time; if the patient's condition was not changed, the head CT was routinely performed 24 hours after IV drip thrombolysis. After exclusion of intracranial hemorrhage, the patients in both groups were treated additionally by the platelet aggregation drug on the basis of their original treatment. The National Institutes of Health Stroke Scale (NIHSS) scores, Bartherl index (BI) scores were recorded before and after treatment, and the recovery situation of neurological function, hemorrhage conversion rate, mortality and adverse reactions were observed after thrombolysis. Results After treatment, the NIHSS scores were lower, and the BI index scores were higher than those before treatment in the two groups, and the change in the observation group after 14 days of treatment was more significant (NIHSS score: 3.87±3.46 vs. 7.37±4.18, BI score: 87.38±9.34 vs. 75.67±8.05, both P < 0.05); the total effective rate of the observation group was significantly higher than that of the control group [73.2% (30/41) vs. 55.0% (22/40), P < 0.05], the rate of bleeding conversion rate was lower than that of the control group [2.4% (1/41) vs. 7.5% (3/40), P < 0.05], the difference in fatality rate between the two groups was not statistically significant [2.4% (1/41) vs. 2.5% (1/40), P > 0.05]. Conclusion The clinical therapeutic effect of butylphthalide injection is relatively good for treatment of patients with ultra-early ACI.
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Objective To observe the effect of early using butylphthalide injection before and after thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) on the clinical prognosis of patients with ultra-early acute cerebral infarction (ACI). Methods A prospective study was conducted, 81 patients with ACI admitted to the Department of Neurology of Tangshan Worker's Hospital from September 2014 to March 2016 were enrolled, and they were divided into a control group (40 cases) and an observation group (41 cases) according to the random number table. Both groups were given routine treatments, such as drugs for lowering blood pressure and blood sugar, decreasing blood lipid to stabilize plaque, neuroprotection, activating blood circulation and removing blood stasis, etc. On the basis of conventional treatment, the control group was directly treated with rt-PA intravenous (IV) thrombolytic therapy according to the guidelines of thrombolytic therapy; in the observation group, the patients immediately underwent CT head examination after admission to decide whether the thrombolytic therapy was necessary, if the therapy was decided to be done, during doctors waiting for the laboratory results or transferring patients, IV drip of butylphthalide sodium chloride 100 mL. After IV drip thrombolytic therapy, if the disease condition was stabilized, the head CT was re-examined to exclude intracranial hemorrhage, if no such hemorrhage, IV drip of butylphthalide sodium chloride 100 mL was continuously given, twice daily for consecutive 14 days with the interval between the two times of IV drip being 7 hours daily. When patient's condition was changed, the re-examination of head CT could be done at any time; if the patient's condition was not changed, the head CT was routinely performed 24 hours after IV drip thrombolysis. After exclusion of intracranial hemorrhage, the patients in both groups were treated additionally by the platelet aggregation drug on the basis of their original treatment. The National Institutes of Health Stroke Scale (NIHSS) scores, Bartherl index (BI) scores were recorded before and after treatment, and the recovery situation of neurological function, hemorrhage conversion rate, mortality and adverse reactions were observed after thrombolysis. Results After treatment, the NIHSS scores were lower, and the BI index scores were higher than those before treatment in the two groups, and the change in the observation group after 14 days of treatment was more significant (NIHSS score: 3.87±3.46 vs. 7.37±4.18, BI score: 87.38±9.34 vs. 75.67±8.05, both P < 0.05); the total effective rate of the observation group was significantly higher than that of the control group [73.2% (30/41) vs. 55.0% (22/40), P < 0.05], the rate of bleeding conversion rate was lower than that of the control group [2.4% (1/41) vs. 7.5% (3/40), P < 0.05], the difference in fatality rate between the two groups was not statistically significant [2.4% (1/41) vs. 2.5% (1/40), P > 0.05]. Conclusion The clinical therapeutic effect of butylphthalide injection is relatively good for treatment of patients with ultra-early ACI.
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Endocytosis is a process by which cells absorb extracellular materials via the inward budding of vesicles formed from the plasma membrane. Receptor-mediated endocytosis is a highly selective process where receptors with specific binding sites for extracellular molecules internalize via vesicles. G protein-coupled receptors (GPCRs) are the largest single family of plasma-membrane receptors with more than 1000 family members. But the molecular mechanisms involved in the regulation of GPCRs are believed to be highly conserved. For example, receptor phosphorylation in collaboration with β-arrestins plays major roles in desensitization and endocytosis of most GPCRs. Nevertheless, a number of subsequent studies showed that GPCR regulation, such as that by endocytosis, occurs through various pathways with a multitude of cellular components and processes. This review focused on i) functional interactions between homologous and heterologous pathways, ii) methodologies applied for determining receptor endocytosis, iii) experimental tools to determine specific endocytic routes, iv) roles of small guanosine triphosphate-binding proteins in GPCR endocytosis, and v) role of post-translational modification of the receptors in endocytosis.
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Humans , Binding Sites , Cell Membrane , Cooperative Behavior , Endocytosis , Glycosylation , Guanosine , Lipoylation , Phosphorylation , Protein Processing, Post-TranslationalABSTRACT
Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the β-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and β-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ.
Subject(s)
Immunoprecipitation , Receptors, Dopamine D3ABSTRACT
PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D₃ receptors (D₃R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D₂ receptor (D₂R) and D₃R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D₂R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D₃R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D₃R functions.
Subject(s)
Autoreceptors , Dopamine Plasma Membrane Transport Proteins , Dopamine , Dopaminergic Neurons , Endocytosis , HandABSTRACT
β-Arrestins are one of the protein families that interact with G protein-coupled receptors (GPCRs). The roles of β-arrestins are multifaceted, as they mediate different processes including receptor desensitization, endocytosis, and G protein-independent signaling. Thus, determining the GPCR regions involved in the interactions with β-arrestins would be a preliminary step in understanding the molecular mechanisms involved in the selective direction of each function. In the current study, we determined the roles of the N-terminus, intracellular loops, and C-terminal tail of a representative GPCR in the interaction with β-arrestin2. For this, we employed dopamine D₂ and D₃ receptors (D₂R and D₃R, respectively), since they display distinct agonist-induced interactions with β-arrestins. Our results showed that the second and third intracellular loops of D₂R are involved in the agonist-induced translocation of β-arrestins toward plasma membranes. In contrast, the N- and C-termini of D₂R exerted negative effects on the basal interaction with β-arrestins.
Subject(s)
Humans , Cell Membrane , Dopamine , Endocytosis , TailABSTRACT
Objective PSGL-1 is specifically expressed in leucocytes.The aim of this study was to explore the changes of myeloid-derived suppressor cells (MDSCs) in the spleen and bone marrow in PSGL-1-deficient mice.Methods PSGL-1 -/-mice were used in the experiment.After identification of the offsprings, flow cytometry was used to test the expression of CD11b and Gr-1 in C57 and PSGL-1 -/-mice.Results Compared with the C57 mice, the expression of MDSCs was up-regulated in the PSGL-1-deficient mice ( P <0.001).Conclusion The expression of MDSCs is upregulated in PSGl-1-deficient mice.