Do antibody CDR loops change conformation upon binding?

Antibodies have increasingly been developed as drugs with over 100 now licensed in the US or EU. During development, it is often necessary to increase or reduce the affinity of an antibody and rational attempts to do so rely on having a structure of the antibody-antigen complex often obtained by modeling. The antigen-binding site consists primarily of six loops known as complementarity-determining regions (CDRs), and an open question has been whether these loops change their conformation when they bind to an antigen. Existing surveys of antibody-antigen complex structures have only examined CDR conformational change in case studies or small-scale surveys. With an increasing number of antibodies where both free and complexed structures have been deposited in the Protein Data Bank, a large-scale survey of CDR conformational change during binding is now possible. To this end, we built a dataset, AbAgDb, that currently includes 177 antibodies with high-quality CDRs, each of which has at least one bound and one unbound structure. We analyzed the conformational change of the Cα backbone of each CDR upon binding and found that, in most cases, the CDRs (other than CDR-H3) show minimal movement, while 70.6% and 87% of CDR-H3s showed global Cα RMSD ≤ 1.0Å and ≤ 2.0Å, respectively. We also compared bound CDR conformations with the conformational space of unbound CDRs and found most of the bound conformations are included in the unbound conformational space. In future, our results will contribute to developing insights into antibodies and new methods for modeling and docking.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects.

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33-104.96% for the maximum plasma concentration (Cmax), 97.21-102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0-t), and 97.22-102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0-∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28-110.69% for the minimal BIS value (BISmin), 99.23-101.17% for the area under the BIS time curve from time 0-60 min after administration (BISAUC0-60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00-125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number: http://www.chinadrugtrials.org.cn/index.html . # CTR20191836.

The threaten of typhoons to the health of residents in inland areas: a study on the vulnerability of residents to death risk during typhoon "Lekima" : In Jinan, China.

BACKGROUND: Studies had suggested increased risk of death of residents was associated with typhoons, particularly coastal regions. However, these findings ignored the impact of inland typhoons on the health of residents, especially the indirect death risk caused by typhoons. This study aimed to investigate the acute death risk of residents during inland typhoon Lekima in Jinan, further identify vulnerable populations and areas. METHODS: We selected the daily death from 11 to 27th August 2019 in Jinan as case period, and conducted a time-stratified case-crossover design to match the contemporaneous data from 2016 to 2018 as control period. We used the generalized linear Poisson models to estimate the related effects of death risk during typhoon Lekima and lag days. RESULTS: During the Lekima typhoon month, there were 3,366 deaths occurred in Jinan. Compared to unexposed periods, the acute death risk of non-accidental diseases (especially circulatory diseases), female and the older adults increased significantly in the second week after the typhoon. The maximum significant effect of circulatory disease deaths, female and older adult deaths were appeared on lag9, lag9, and lag13 respectively. And the typhoon-associated RR were 1.19 (95%CI:1.05,1.34), 1.28 (95%CI:1.08,1.52), and 1.22 (95%CI:1.06,1.42) respectively. The acute death risk of residents living in TQ and CQ increased significantly on Lag2 and Lag6 after the typhoon, respectively, while those living in LX, LC, HY, JY, and SH occurred from Lag 8 to Lag 13 after the typhoon. LC lasted the longest days. CONCLUSIONS: Typhoons would increase the vulnerability of residents living in Jinan which mainly occurred from the seventh day after the typhoon. Residents suffering from non-accidental diseases (circulatory diseases), female and the older adults were more vulnerable. The vulnerability of TQ and CQ occurred on Lag2 and Lag6 after typhoon Lekima, respectively, and the other areas except ZQ and PY occurred from Lag 8 to Lag 13. LC lasted the longest duration. Our findings emphasized the importance of the emergency response, which would help policymakers to identify vulnerable regions and populations accurately during typhoons and formulate the emergency response plan.

Quantifying the effects of cold waves on carbon monoxide poisoning: A time-stratified case-crossover study in Jinan, China.

Background: Previous studies have shown that carbon monoxide (CO) poisoning occurs mostly in winter and is associated with severe cold weather (e.g., ice storms, temperature drops). However, according to previous studies, the impact of low temperature on health has a delayed effect, and the existing research cannot fully reveal the delayed effect of cold waves on CO poisoning. Objectives: The purpose of this study is to analyze the temporal distribution of CO poisoning in Jinan and to explore the acute effect of cold waves on CO poisoning. Methods: We collected emergency call data for CO poisoning in Jinan from 2013 to 2020 and used a time-stratified case-crossover design combined with a conditional logistic regression model to evaluate the impact of the cold wave day and lag 0-8 days on CO poisoning. In addition, 10 definitions of a cold wave were considered to evaluate the impact of different temperature thresholds and durations. Results: During the study period, a total of 1,387 cases of CO poisoning in Jinan used the emergency call system, and more than 85% occurred in cold months. Our findings suggest that cold waves are associated with an increased risk of CO poisoning in Jinan. When P01, P05, and P10 (P01, P05, and P10 refer to the 1st, 5th, and 10th percentiles of the lowest temperature, respectively) were used as temperature thresholds for cold waves, the most significant effects (the maximum OR value, which refers to the risk of CO poisoning on cold wave days compared to other days) were 2.53 (95% CI:1.54, 4.16), 2.06 (95% CI:1.57, 2.7), and 1.49 (95% CI:1.27, 1.74), respectively. Conclusion: Cold waves are associated with an increased risk of CO poisoning, and the risk increases with lower temperature thresholds and longer cold wave durations. Cold wave warnings should be issued and corresponding protective policies should be formulated to reduce the potential risk of CO poisoning.

Identification of LncRNA-miRNA-mRNA ceRNA network in hypoxia-induced HTR-8/SVneo cells for preeclampsia.

Preeclampsia (PE) is a common pregnancy complication, and placental hypoxia is one of its causes. We aimed to identify the transcriptional profile and construct a long non-coding RNAs (lncRNA)-centered competing endogenous RNAs (ceRNA) network in hypoxia-induced HTR8/SVneo cells. We used datasets from the GEO database to identify important pathways in PE. We performed microarray profiling and functional analysis to identify differentially expressed long non-coding RNAs (lncRNAs), differentially expressed profiles of microRNA (miRNAs), and differentially expressed profiles of messenger RNA (mRNAs) in hypoxia-induced HTR8/SVneo cells. The candidates were validated using quantitative reverse transcription polymerase chain reaction. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were performed to understand the functional significance of differentially expressed genes. Finally, we constructed an lncRNA-centered ceRNA network. Several hub genes were validated both in placentas from PE and normal pregnancy, and in hypoxia-induced HTR8/SVneo cells. The hypoxic response pathway was involved in the pathophysiology of PE. Subsequently, we identified 536 differentially expressed profiles of lncRNAs (183 upregulated and 353 downregulated), 46 differentially expressed profiles of miRNAs (35 upregulated and 11 downregulated), and 2782 differentially expressed profiles of mRNAs (DEmRNAs) (1031 upregulated and 1751 downregulated) in hypoxia-induced HTR8/SVneo cells. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed potential pathways affected by these genes, such as angiogenesis, the HIF-1 signaling pathway, and the PI3K-Akt signaling pathway. The ceRNA network comprised 35 lncRNAs, 11 miRNAs, 27 mRNAs, and 2 hub lncRNAs, which might play a vital role in placental functions and PE. Our results revealed the transcriptome profile and constructed an lncRNA-centered ceRNA network in hypoxia-induced HTR8/SVneo cells, thereby providing potential therapeutic targets for PE.

Nitidine chloride regulates cell function of bladder cancer in vitro through downregulating Lymphocyte antigen 75.

Nitidine chloride (NC) is effective on cancer in many tumors, but its effect on bladder cancer (BC) is unknown. We conducted cell function experiments to verify the antineoplastic effect of NC on BC cell lines (5637, T24, and UM-UC-3) in vitro. Then, mRNAs of NC-treated and NC-untreated BC cells were extracted for mRNA sequencing. Differentially expressed genes (DEGs), expression analysis, and drug molecular docking were conducted to discover the target gene of NC. Finally, functional enrichment was analyzed to explore the underlying mechanisms. NC dramatically inhibited proliferation, migration, and invasion, and it induced apoptosis and arrested the S and G2/M phases of BC cell lines. Lymphocyte antigen 75 (LY75) appeared to be the target of NC. LY75 was highly expressed and had the ability to distinguish BC tissue from non-cancerous tissue. Then, drug molecular docking confirmed the targeting relationship between NC and LY75. Gene enrichment analysis showed that the downregulated genes, after being treated with NC, were mainly enriched in pathways relevant to cell pathophysiological processes. NC inhibits BC cell proliferation, migration, and invasion, induces apoptosis, and arrests cell cycles by downregulating the expression of LY75. This study provides molecular and theoretical bases for NC treatment of BC.

Financial development, technological innovation and urban-rural income gap: Time series evidence from China.

The main purpose of the paper is to investigate the relationship between technological innovation and income inequality for China based on the financial Kuznets curve (FKC) hypothesis. The study uses time-series data from 1985 to 2019. We employ the Johansen cointegration, ARDL model and VECM Granger causality techniques to analyze the links between the variables. We also use the DOLS, FMOLS and CCR mechanisms to estimate the long-run parameters. The paper finds that the FKC is valid for China's economy in the long run. Technological innovation positively affects the urban-rural income gap, while there is an inverted-U shaped between financial development and the urban-rural income gap. The relationship between financial development and the urban-rural income gap is bi-directional causality. Technological innovation and the urban-rural income gap cause each other. Empirical results suggest a twofold policy meaning: i) to further the financial system and ii) to eliminate the adverse impacts of technological innovations on income distribution.

ANP promotes HTR-8/SVneo cell invasion by upregulating protein kinase N 3 via autophagy inhibition.

Preeclampsia is a gestational disease characterized by two major pathological changes-shallow trophoblast invasion and impaired spiral artery remodeling. Atrial natriuretic peptide (ANP) is a kind of peptide hormone that regulates blood pressure, while the lack of active ANP participates in preeclampsia pathogenesis. However, the underlying mechanism of how ANP modulates trophoblasts function remains unclarified. Here, we performed isobaric tags for relative and absolute quantification (iTRAQ) in ANP-treated HTR-8/SVneo cells and identified Protein Kinase 3 (PKN3) as the downstream factor of ANP, which was downregulated in preeclamptic placenta. Chromatin immunoprecipitation analysis and luciferase assays showed that NFYA was one of the transcription factors for the PKN3 promoter, which was also regulated by ANP treatment in HTR-8/SVneo cells. Transmission electron microscopy and Western Blotting in HTR-8/SVneo cells indicated that ANP inhibited autophagy via AMPK-mTORC1 signaling, while excess autophagy was observed in preeclamptic placenta. The increased expression of PKN3 and enhanced cell invasion ability in HTR-8/SVneo cells induced by ANP could be abolished by autophagy activation or transfection with PKN3 shRNA or NFYA shRNA or NPR-A shRNA via regulating the invasion-related genes and the epithelial mesenchymal transition molecules. Our results demonstrated that ANP could enhance trophoblast invasion by upregulating PKN3 via NFYA promotion through autophagy inhibition in an AMPK/mTORC1 signaling-dependent manner.

Extreme cold weather and circulatory diseases of older adults: A time-stratified case-crossover study in jinan, China.

OBJECTIVES: We aimed to investigate the acute effect of extreme cold weather on circulatory disease mortality of older adults in Jinan, with individual and regional-scale characteristics as subgroup analyses to further identify vulnerable populations. METHODS: This study contained the death data of Jinan from 2011 to 2020 (Nov-Mar). A time-stratified case-crossover method was used to estimate the effects of extreme cold weather and lags 0-8 days, controlling for holiday and relative humidity. To evaluate the impact of different durations and thresholds of extreme cold weather, we considered 4 cold day and 12 cold wave definitions RESULTS: Our results showed an increase in circulatory disease deaths under several definitions. The number of older adults died of circulatory diseases totaled 92,119 during the study period. In the definitions of cold day, the maximum significant effect ranging from 1.08 (95% CI: 1.03,1.14) to 1.13 (95% CI: 1.04,1.24) and appeared on Lag5 or Lag6. In the definitions of cold wave, the maximum significant effect ranging from 1.07 (95% CI: 1.02, 1.12) to 1.14 (95% CI: 1.03, 1.25). The cold effect is mainly attributable to cold day rather than an added effect related to the duration. Our research confirmed that extreme cold weather had a stronger impact on women [maximum effects with an OR of 1.21 (95% CI: 1.08, 1.36) in P1, 1.19 (95% CI: 1.05, 1.36) in M12)], and the effect gradient increased with age. CONCLUSIONS: Our findings support the evidence on the impact of extreme cold weather on circulatory disease mortality and provide a basis for policymakers to select target groups to develop policies and reduce the public health burden.

Spatiotemporal evolution characteristics of coordinated development of urbanization and ecological environment in eastern Russia-Perspectives from the 3D global trend and 2D plane analysis.

Under the background of "the Belt and Road" and "the economic corridor of China, Mongolia and Russia" initiatives, it has great value to study the temporal and spatial evolution characteristics of the coordinated development between the urbanization and ecological environment in eastern Russia (the Siberian Federal District and the Far East Federal District). In this paper, we studied the urbanization development level, eco-environment development level, and their coupling coordinated development degree during 2005-2018 in the eastern Russia from the perspectives of the 3D global trend and 2D plane analysis. First, combining with the Population-Economic-Sociology and Pressure-State-Response models, the urbanization development level and eco-environment development level were calculated by the comprehensive weighting method of entropy weight and variation coefficient for eastern Russia. Second, the coupling coordinated development degree of the urbanization development level and eco-environment development level was measured by the coupling coordination model for eastern Russia. Finally, the spatial differentiation of the urbanization development level, the eco-environment development level and their coupling coordinated development degree was performed respectively by the 3D global trend and 2D plane analysis using ArcGIS. The results are as following. First, the comprehensive urbanization development level of eastern Russia has increased from 2005 to 2018, and the economic urbanization is the main factor that affects the urbanization development in eastern Russia. The comprehensive eco-environment development level of eastern Russia has decreased from 2005 to 2018, and the eco-environment pressure is the main factor that affects the eco-environment development in eastern Russia. The coupling coordination degree of the urbanization development and eco-environment development has increased from 2005 to 2018. However, it is still in the uncoordinated stage. Second, from 2005 to 2018, the urbanization development level of the Siberian Federal District is higher than that of the Far East Federal District. The eco-environment development level of the Siberian Federal District is balanced to that of the Far East Federal District. The coupling coordination degree of the Siberian Federal District is higher than that of the Far East Federal District. Among the Siberian and Far East Federal Districts, most of the federal subjects belong to the uncoordinated stage of the urbanization development and the eco-environment development. Third, the urbanization development level, the eco-environment development level, and their coupling coordinated development level are all spatially imbalanced in the eastern Russia, which show the "High West, Low East" and "High Center, Low North and Low South" spatial pattern from the perspectives of the 3D global trend and 2D plane analysis. The areas with high levels are concentrated in the Novosibirsk Region, Altay Territory, Kemerovo Region, Krasnoyarsk Territory, and Irkutsk Region. The areas with low ones are mostly in the Republic of Altay and Chukotka Autonomous Area. Finally, we suggest policies and strategies that can boost the growth and development of the urbanization and the eco-environment in the Sino-Russian border areas.

Clinical esthetic comparison between monolithic high-translucency multilayer zirconia and traditional veneered zirconia for single implant restoration in maxillary esthetic areas: Prosthetic and patient-centered outcomes.

Background/purpose: Clinical esthetic evidence for the performance of monolithic high-translucency multilayer zirconia is lacking. The aim of this study was to compare monolithic high-translucency multilayer zirconia with traditional veneered zirconia in clinical situation. Material and methods: A total of 30 participants who were provided with both monolithic zirconia crowns (Group 1) and traditional veneered crowns (Group 2) for single implant restoration in maxillary esthetic areas were enrolled. Patients' subjective outcome (Visual Analog Scale, VAS) were recorded. Photos were taken and then evaluated by 9 evaluators with Pink and White Esthetic Score (WES). Wilcoxon signed rank test was used for comparison between Group 1 and Group 2 in VAS, WES and five variables in WES. Kendall's coefficient of concordance test was used to calculate inter-rater reliability of WES variables. Spearman correlation was used to analyze association between patients' outcome and evaluators' scores. Results: There was no significant difference in patients' subjective outcome between monolithic zirconia and traditional veneered crowns: overall VAS were 9.0 (8.0-9.0) and 9.0 (8.5-9.5), respectively (P > 0.05). However, in professional view, significant difference between Group 1 and Group 2 in WES was observed: 7.5 (6.0-8.0) and 8.0 (6.5-8.5), respectively (P < 0.05). Kendall's test showed, among WES variables, translucency demonstrated the highest agreement. Professionally reported evaluations did not correlate with patient-reported outcomes (Spearman correlation were 0.246 and 0.224 for Group 1 and Group 2, respectively). Conclusion: Within the limitation of this study, it can be concluded that monolithic high-translucency multilayer zirconia restoration might be a treatment modality.

Safety, Tolerability, and Pharmacokinetic Study of 101BHG-D01 Nasal Spray, a Novel Long-Acting and Selective Cholinergic M Receptor Antagonist, in Healthy Chinese Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation, First-In-Human Study.

BACKGROUND AND OBJECTIVE: 101BHG-D01 nasal spray is the first novel long-acting cholinergic M receptor antagonist under development to treat rhinorrhea in rhinitis. This first-in-human study aimed to evaluate the safety, tolerability, and pharmacokinetics of 101BHG-D01 nasal spray following single intranasal doses in healthy Chinese subjects. METHODS: A randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in healthy Chinese volunteers after intranasal doses of 101BHG-D01 nasal spray or placebo ranging from 40 µg to 960 µg (total of six doses). Blood samples were collected at scheduled time points, and plasma concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t), the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration (Tmax), and the elimination half-life (t1/2). Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), anterior rhinoscopy, ophthalmic examination, and ambulatory ECG monitoring. RESULTS: Following single intranasal dosing, 101BHG-D01 was rapidly absorbed with a median Tmax of 0.34-0.50 h and eliminated slowly with a mean t1/2 ranging from 4.29 to 46.76 h for different dose groups. The Cmax and AUC of 101BHG-D01 increased linearly across the examined dose range of 40-960 µg. 101BHG-D01 nasal spray was well tolerated, all AEs were mild, and no serious adverse events occurred during the study. CONCLUSIONS: 101BHG-D01 nasal spray was safe and well tolerated in healthy Chinese subjects when administered intranasally in single escalating doses. The mean Cmax and AUC increased proportionally to the studied dose. The pharmacokinetic, safety, and tolerability profiles of 101BHG-D01 nasal spray indicate that it is a good candidate for further development as a treatment for rhinorrhea in rhinitis.

Evolution characteristics of temporal and spatial pattern of Russian economic differences since the 21st century.

Under the background of "the Belt and Road" and "the economic corridor of China, Mongolia and Russia" initiatives, it is of great significance to study the temporal and spatial economic pattern in the Russian Federation. Based on the economic development difference index, regional economic grade index, global trend analysis tool and spatial autocorrelation model, this paper analyzes the temporal and spatial pattern evolution characteristics of Russian economic differences from 2002 to 2020. The results are as following. First, although the economic imbalance among various federal subjects has been decreasing, the economic polarization has been still severe between the prosperous developed regions and the stagnant backward regions during 2002-2020. Russia's economy shows a trend of changing from significant positive correlation in strong agglomeration space to positive correlation in weak agglomeration space, and then to random distribution. Second, there has been great differences of the economic development among various federal subjects. The economic grade of the Russian federal subjects presents a significant spatial differentiation pattern. The Russian Federation's economic resources are concentrated in the first-class federal subject (Moscow City), second-class federal subjects (Tumen Region, Moscow Region and Saint-Petersburg city) and a few third-class federal subjects (Yamalo-Nenetsky Autonomous Area, Khanty-Mansiysky Autonomous Area, Republic of Tatarstan, Krasnodar Territory, Sverdlovsk Region, etc). Third, the Russian Federation's economy presents "High Core, Low Periphery", "High West, Low East" and "High south, Low north" spatial differentiation pattern. The economic hot regions coincide with the high-class economic regions, which are mainly distributed in the contiguous areas of Ural Federal District and Volga Federal District, as well as the Moscow City, Moscow Region, Saint-Petersburg city, Krasnodar Territory and Rostov Region. The economic cold regions coincide with the low-class economic regions, which are mainly located in the Far East Federal District, the east of Siberian Federal District, the north of North West Federal District and the south of North-Caucasian Federal District. Finally, we suggest the recommendation for policy makers in Russia. And we propose the future research ideas.

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia.

Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1 (SIRT1), a class III histone deacetylase, is associated with the regulation of various pathophysiological processes, including inflammation, immune response, metabolism, and autophagy. However, the effect of SIRT1 in the pathogenesis of pre-eclampsia remains to be elucidated. In this study, we found that the expression of SIRT1 was relatively lower in the placentas and serum samples of pre-eclampsia patients. Typical pre-eclampsia-like symptoms, such as hypertension, proteinuria, fetal growth restriction, kidney injury, and a narrow placental labyrinth layer, were observed in SIRT1 knockdown (SIRT1+/-) mice. Of note, these performances could be improved after the intraperitoneal injection of SIRT1 agonist SRT2104. More importantly, we found that the efficacy of progesterone on attenuating symptoms of PE was profoundly better than that of metformin in SIRT1+/- mice. In addition, our results suggested that progesterone can promote the invasion and inhibit the apoptosis of trophoblasts. These data suggest that SIRT1 plays an important role in pre-eclampsia and that progesterone alleviates pre-eclampsia-like symptoms mediated by SIRT1 deficiency.

Bioequivalence Study of Palbociclib Capsules in Healthy Chinese Subjects Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinase 4/6 used for the treatment of advanced breast cancer. This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of palbociclib capsules in healthy Chinese subjects under fasting and fed conditions and evaluated the bioequivalence of two palbociclib products to obtain sufficient evidence for the marketing approval of the new generic drug. METHODS: A randomized, open-label, two-period crossover study was conducted in healthy Chinese volunteers under both fasting and fed conditions (30 subjects/condition). Eligible healthy subjects received a single 125-mg dose of the palbociclib test or reference formulation followed by a 14-day washout period. Serial blood samples were collected at scheduled timepoints, and plasma concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. A non-compartment method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC0-t), the AUC from time 0 to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration, and the elimination half-life. The geometric mean ratios and the corresponding 90% confidence intervals of palbociclib were acquired for the bioequivalence analysis. Safety and tolerability were assessed by monitoring adverse events, laboratory assessments, vital signs, physical examinations, and 12-lead electrocardiograms. RESULTS: Under the fasting condition, the pharmacokinetic parameter values of the test formulation were similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 94.35-103.82% for Cmax, 94.79-103.26% for AUC0-t, and 94.82-103.38% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. Meanwhile, under the fed condition, the pharmacokinetic parameter values of the test formulation were also similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 96.65-103.56% for Cmax, 98.06-103.61% for AUC0-t, and 97.88-103.46% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. The test and reference products were well tolerated, and no serious adverse events occurred during the study. CONCLUSIONS: Pharmacokinetic bioequivalence of palbociclib in healthy subjects was established between the palbociclib test formulation and the reference formulation under fasting and fed conditions according to predetermined regulatory criteria. The two formulations were safe and well tolerated.

Intra- and inter-observer agreements in detecting peri-implant bone defects between periapical radiography and cone beam computed tomography: A clinical study.

BACKGROUND/PURPOSE: Information regarding agreements between periapical radiograph (PA) and cone beam computed tomography (CBCT) in detecting peri-implant defect is still scarce. The aim of this clinical study was to compare agreements between PA and CBCT in detecting peri-implant bone defect. MATERIALS AND METHODS: This retrospective clinical study enrolled 32 patients with both PA and CBCT filmed right after implant placement. Four modalities were used for film reading: PA1 (original), PA2 (enhanced brightness/contrast), CBCT1 (selected axial and mesial-distal direction images) and CBCT2 (all data with software). 2 experienced and 2 inexperienced observers scored all films. Intra- and inter-observer agreements were estimated with Cohen's kappa coefficient. Categorized agreements were compared and differences among four modalities were calculated. RESULTS: Agreements of PA were better than CBCT when detecting peri-implant bone defects in inter-observer agreements (median kappa 0.471 vs. 0.192; p = 0.016). Moreover, agreements in experienced observers were better than inexperienced observers (median kappa 0.883 vs. 0.567; p < 0.001). There was significant difference among four modalities except for experienced observer 2 (p = 0.218). CONCLUSION: Agreements of PA are better than CBCT when detecting peri-implant bone defects, especially for inter-observer agreements. Experienced observers are more consistent in assessment than inexperienced ones.

Influence of Different Factors on the Accuracy of Digital Impressions of Multiple Implants: An In Vitro Study.

PURPOSE: To investigate the effect of implant angulation, non-free-end partial edentulism, and number of scan bodies on the accuracy of digital impressions of multiple implants in partially edentulous arches. MATERIALS AND METHODS: Four reference models of partially edentulous mandibles with implants (RM1, RM2, RM3, and RM4) representing different intraoral situations were each scanned 10 times by an intraoral scanner. Reference scans were obtained by a laboratory scanner. Test scans were compared with reference scans to obtain the distance deviations (Δd) and angular deviations (Δθ) between scan bodies for trueness assessment. Differences among the repeated test scans of each model were measured and recorded as Δdp and Δθp for precision assessment. The Student t test (α = .05) was used to compare Δd, Δθ, Δdp, and Δθp of different reference models, including RM2 vs RM1 (effect of non-free-end partial edentulism), RM3 vs RM1 (effect of implant angulation), and RM4 vs RM1 (effect of number of scan bodies). RESULTS: The implant with 17-degree angulation in RM3 showed significantly lower Δd, Δθ, and Δθp compared with the parallel implant in RM1 (Δd: P = .0382, Δθ: P = .0267, Δθp: P = .0417). The RM2 of non-free-end partial edentulism had lower distance and angular deviations than RM1, but without a significant difference. The number of scan bodies had no significant effect on the Δd, Δθ, Δdp, and Δθp of RM4 and RM1. CONCLUSION: Angulated implants showed better accuracy of digital impressions in partially edentulous arches compared with parallel implants. Non-free-end partial edentulism was attributed to improved accuracy, while the number of scan bodies showed no effect.

Improved response of human gingival fibroblasts to titanium coated with micro-/nano-structured tantalum.

OBJECTIVES: This study aims to evaluate the ability of tantalum-coated titanium to improve human gingival fibroblasts' adhesion, viability, proliferation, migration performance, and the potential molecular mechanisms. MATERIALS AND METHODS: Titanium plates were divided into two groups: (1) no coating (Ti, control), (2) Tantalum-coated titanium (Ta-coated Ti). All samples were characterized by scanning electronic microscopy, surface roughness, and hydrophilicity. Fibroblasts' performance were analyzed by attached cell number at 1 h, 4 h, and 24 h, morphology at 1 h and 4 h, viability at 1 day, 3 days, 5 days, and 7 days, recovery after wounding at 6 h, 12 h, and 24 h. RT-PCR, western blot were applied to detect attachment-related genes' expression and protein synthesis at 4 h and 24 h. Student's t test was used for statistical analysis. RESULTS: Tantalum-coated titanium demonstrates a layer of homogeneously distributed nano-grains with mean diameter of 25.98 (± 14.75) nm. It was found that after tantalum deposition, human gingival fibroblasts (HGFs) adhesion, viability, proliferation, and migration were promoted in comparison to the control group. An upregulated level of Integrin ß1 and FAK signaling was also detected, which might be the underlying mechanism. CONCLUSION: In the present study, adhesion, viability, proliferation, migration of human gingival fibroblasts are promoted on tantalum-coated titanium, upregulated integrin ß1 and FAK might contribute to its superior performance, indicating tantalum coating can be applied in transmucosal part of dental implant. CLINICAL SIGNIFICANCE: Tantalum deposition on titanium surfaces can promote human gingival fibroblast adhesion, accordingly forming a well-organized soft tissue sealing and may contribute to a successful osseointegration.

Accuracy of dynamic navigation in implant surgery: A systematic review and meta-analysis.

OBJECTIVE: To assess the accuracy of dynamic computer-assisted implant surgery. MATERIALS AND METHODS: An electronic search up to March 2020 was conducted using PubMed, Embase, and the Cochrane Central Register of Controlled Trial to identify studies using dynamic navigation in implant surgery, and additional manual search was performed as well. Clinical trials and model studies were selected. The primary outcome was accuracy. A single-arm meta-analysis of continuous data was conducted. Meta-regression was utilized for comparison on study design, guidance method, jaw, and systems. RESULTS: Ten studies, four randomized controlled trials (RCT) and six prospective studies, met the inclusion criteria. A total of 1,298 drillings and implants were evaluated. The meta-analysis of the accuracy (five clinical trials and five model studies) revealed average global platform deviation, global apex deviation, and angular deviation were 1.02 mm, 95% CI (0.83, 1.21), 1.33 mm, 95% CI (0.98, 1.67), and 3.59°, 95% CI (2.09, 5.09). Meta-regression shown no difference between model studies and clinical trials (p = .295, 0.336, 0.185), drilling holes and implant (p = .36, 0.279, 0.695), maxilla and mandible (p = .875, 0.632, 0.281), and five different systems (p = .762, 0.342, 0.336). CONCLUSION: Accuracy of dynamic computer-aided implant surgery reaches a clinically acceptable range and has potential in clinical usage, but more patient-centered outcomes and socio-economic benefits should be reported.

Half depletion of Foxp3+ regulatory T cells by diphtheria toxin for long-term study in vivo.

Depletion of regulatory T cells (Tregs) is an appropriate approach to study the function of Tregs in vivo, and most previous studies have focused on complete depletion. The purpose of the current study was to determine an appropriate dose and timing for half depletion of Tregs in vivo. DETREG (DEpletion of REGulatory T cells) mice were produced and injected with different doses of diphtheria toxin (DT) for 7 days and 14 days. The mice were then sacrificed to collect the spleen and mesenteric lymph nodes (MLN) for analysis using flow cytometry. Foxp3+eGFP+ cells were significantly reduced by DT injection. A dose of 5 ug/kg DT led to half depletion and no deaths. A DT dose of 25, 50, or 100 ug/kg led to a progressively higher depletion rate but also a higher mortality rate. In conclusion, a low dose of DT is effective for half depletion of Tregs and long-term study. Half depletion of Tregs may become a new method for the future study of Tregs in vivo.