TET1-TRPV4 Signaling Contributes to Bone Cancer Pain in Rats.

Bone cancer pain (BCP) is excruciating for cancer patients, with limited clinical treatment options and significant side effects, due to the complex and unclear pathogenesis of bone cancer pain. Peripheral sensitization in dorsal root ganglion (DRG) neurons is a recognized cellular mechanism for bone cancer pain. The pathological mechanism of chronic pain is increasingly being affected by epigenetic mechanisms. In this study, we unbiasedly showed that the DNA hydroxymethylase ten-eleven translocation 1 (TET1) expression was significantly increased in the L4-6 DRG of BCP rats and ten-eleven translocation 2 (TET2) expression did not change significantly. Notably, TET1 inhibition by intrathecal injection of Bobcat339 (a TET1 inhibitor) effectively relieved mechanical hyperalgesia in BCP rats. Peripheral sensitization in chronic pain relies on the activation and overexpression of ion channels on neurons. Here, we demonstrated that TRPV4, one of the transient receptor potential ion channel family members, was significantly elevated in the L4-6 DRG of BCP rats. In addition, TRPV4 inhibition by intrathecal injection of HC067047 (a TRPV4 inhibitor) also significantly attenuated mechanical hyperalgesia in BCP rats. Interestingly, we found that TET1 inhibition downregulated TRPV4 expression in the L4-6 DRG of BCP rats. As a result, these findings suggested that TET1 may contribute to bone cancer pain by upregulating TRPV4 expression in the L4-6 DRG of BCP rats and that TET1 or TRPV4 may become therapeutic targets for bone cancer pain.

GDNF promotes the proliferation and osteogenic differentiation of jaw bone marrow mesenchymal stem cells via the Nr4a1/PI3K/Akt pathway.

How to efficiently regenerate jawbone defects caused by trauma, jaw osteomyelitis, tumors, or intrinsic genetic diseases is still challenging. Ectoderm-derived jawbone defect has been reported to be regenerated by selectively recruiting cells from its embryonic origin. Therefore, it is important to explore the strategy for promoting ectoderm-derived jaw bone marrow mesenchymal stem cells (JBMMSCs) on the repair of homoblastic jaw bone. Glial cell-derived neurotrophic factor (GDNF) is an important growth factor and is essential in the process of proliferation, migration and differentiation of nerve cells. However, whether GDNF promoting the function of JBMMSCs and the relative mechanism are not clear. Our results showed that activated astrocytes and GDNF were induced in the hippocampus after mandibular jaw defect. In addition, the expression of GDNF in the bone tissue around the injured area was also significantly increased after injury. Data from in vitro experiments demonstrated that GDNF could effectively promote the proliferation and osteogenic differentiation of JBMMSCs. Furthermore, when implanted in the defected jaw bone, JBMMSCs pretreated with GDNF exhibited enhanced repair effect compared with JBMMSCs without treatment. Mechanical studies found that GDNF induced the expression of Nr4a1 in JBMMSCs, activated PI3K/Akt signaling pathway and then enhanced the proliferation and osteogenic differentiation capacities of JBMMSCs. Our studies reveal that JBMMSCs are good candidates for repairing jawbone injury and pretreated with GDNF is an efficient strategy for enhancing bone regeneration.

Model-Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti-Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof-of-concept part I of the study demonstrated significant treatment effects, part II (dose-ranging) revealed an unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A 1-compartment PopPK model with first-order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E-R relationship; however, this was driven by data from part I. Part II-only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall, and in various subpopulations. No apparent E-R relationships were observed for the investigated safety end points. The PopPK and E-R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement.

Population Pharmacokinetics and Exposure-Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease.

PURPOSE: Ustekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure-response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies. METHODS: Serum ustekinumab concentration-time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n = 1910) and maintenance (n = 387) treatment. FINDINGS: Ustekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t1/2 was 19 days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values. IMPLICATIONS: In patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ∼6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. CLINICALTRIALS: gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations.

OBJECTIVES: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA. METHODS: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). RESULTS: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. CONCLUSIONS: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. CLINICAL TRIAL REGISTRATION: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

Ectoderm-derived frontal bone mesenchymal stem cells promote traumatic brain injury recovery by alleviating neuroinflammation and glutamate excitotoxicity partially via FGF1.

BACKGROUND: Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model. METHODS: A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits. Ectoderm-derived FbMSCs were isolated from the frontal bone and their characteristics were assessed using multiple differentiation assays, flow cytometry and microarray analysis. Brain repairment and functional recovery were analyzed at different days post-injury with or without FbMSC application. Behavioral tests were performed to assess learning and memory improvements. RNA sequencing analysis, immunofluorescence staining, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were used to examine inflammation reaction and neural regeneration. In vitro co-culture analysis and quantification of glutamate transportation were carried out to explore the possible mechanism of neurogenesis and functional recovery promoted by FbMSCs. RESULTS: Ectoderm-derived FbMSCs showed fibroblast like morphology and osteogenic differentiation capacity. FbMSCs were CD105, CD29 positive and CD45, CD31 negative. Different from mesoderm-derived MSCs, FbMSCs expressed the ectoderm-specific transcription factor Tfap2ß. TBI mice showed impaired learning and memory deficits. Microglia and astrocyte activation, as well as neural damage, were significantly increased post-injury. FbMSC application ameliorated the behavioral deficits of TBI mice and promoted neural regeneration. RNA sequencing analysis showed that signal pathways related to inflammation decreased, whereas those related to neural activation increased. Immunofluorescence staining and qRT-PCR data revealed that microglial activation and astrocyte polarization to the A1 phenotype were suppressed by FbMSC application. In addition, FGF1 secreted from FbMSCs enhanced glutamate transportation by astrocytes and alleviated the cytotoxic effect of excessive glutamate on neurons. CONCLUSIONS: Ectoderm-derived FbMSC application significantly alleviated neuroinflammation, brain injury, and excitatory toxicity to neurons, improved cognition and behavioral deficits in TBI mice. Therefore, ectoderm-derived FbMSCs could be ideal therapeutic candidates for TBI which mostly affect cells from the same embryonic origins as FbMSCs.

OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma.

PURPOSE: Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutic approaches to prevent recurrence are needed. EXPERIMENTAL DESIGN: We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2-high and OLIG2-low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models. RESULTS: We found that MYC-associated MB can be stratified into OLIG2-high and OLIG2-low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2-low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2-high tumors were resistant to radiation and consistently developed recurrence. In OLIG2-high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2- tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual-resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells. CONCLUSIONS: Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.

Population pharmacokinetics analysis of guselkumab in healthy subjects and patients with psoriatic arthritis, plaque psoriasis and palmoplantar pustulosis.

AIMS: Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin 23, is approved for the treatment of plaque psoriasis (PsO) and psoriatic arthritis (PsA), palmoplantar pustulosis (PPP), generalized pustular psoriasis, and erythrodermic psoriasis in various countries. The purpose of this analysis was to develop a comprehensive population pharmacokinetic (PK) model for guselkumab to determine whether PK differs across different disease populations and healthy subjects. METHODS: A nonlinear mixed-effects modelling approach was used to analyse 23 097 serum PK samples obtained from 2623 healthy subjects and patients with PsO, PsA and PPP across 9 phase 1-3 clinical trials. RESULTS: Guselkumab concentrations were adequately described by a 2-compartment linear PK model with first-order absorption and elimination. Clearance (CL), central and peripheral volume of distribution, intercompartmental flow, absorption rate constant and absolute bioavailability estimates were 0.255 L/d, 3.60 L, 1.78 L, 0.369 L/d, 0.313 d-1 and 49.2%, respectively, for a subject weighing 70 kg. Terminal half-life was estimated to be approximately 14.6 days. Body weight was the primary factor affecting CL and central volume of distribution. CL of guselkumab was similar among patients with PsA, PsO and PPP, but CL in disease populations was 11-17% lower than that in healthy subjects after other covariate effects such as body weight were considered. CONCLUSION: The population pharmacokinetic analysis indicated that, after other covariate effects were taken into account, patients with PsO, PsA and PPP had similar PK characteristics, with CL in these disease populations being slightly lower than in healthy individuals.

Integrated Population Pharmacokinetic Analysis of Ustekinumab Across Multiple Immune-Mediated Inflammatory Disease Populations and Healthy Subjects.

BACKGROUND AND OBJECTIVES: Ustekinumab has been approved for the treatment of patients with plaque psoriasis (PSO), psoriatic arthritis (PSA), Crohn's disease (CD), and ulcerative colitis (UC). This study was performed to investigate whether the pharmacokinetics of ustekinumab differ across different disease populations. METHODS: An integrated population pharmacokinetic analysis was conducted to characterize ustekinumab pharmacokinetics across four disease indications (i.e., PSO, PSA, CD, and UC) and healthy subjects. RESULTS: The pooled ustekinumab pharmacokinetic data consisted of 46,970 serum concentrations from 3,217 subjects (n = 356 for PSO, 696 for PSA, 1196 for CD, 823 for UC, and 24 for healthy subjects) in 7 clinical trials following subcutaneous or intravenous ustekinumab administrations. The pharmacokinetics of ustekinumab were adequately described by a two-compartment linear model with first-order absorption and elimination. Ustekinumab clearance (CL) and volume of distribution parameters increased nonlinearly with body weight, and the CL was higher in subjects with lower serum albumin, non-Caucasians, and positive antibodies to ustekinumab. Although CL in subjects with PSO and PSA appeared to be slightly different (- 12.7% and + 8.87%, respectively) from CL in other populations (including CD, UC, and healthy subjects), the model-derived post-hoc pharmacokinetic parameters were generally comparable across the 4 disease populations. Simulations also suggested overall comparable ustekinumab exposure (i.e., trough concentration and AUC) at steady state across the disease populations following the same subcutaneous dose regimen. CONCLUSIONS: Ustekinumab pharmacokinetics are generally comparable across all approved inflammatory-mediated indications and healthy subjects after accounting for the body weight-related pharmacokinetic difference.

Does Autologous Transfusion Decrease Allogeneic Transfusion in Liposuction Surgery of Lymphedema Patients?

Background and Objective: Liposuction is an effective treatment for fat disposition in lymphedema. Blood transfusion has been seldom investigated in lymphedema liposuction surgery. The purpose of the study was to analyze clinical factors associated with blood transfusion in liposuction surgery of lymphedema patients and compare the autologous and allogeneic transfusion patterns. Methods: A total of 1,187 cases of liposuction due to lymphedema were recruited. Demographic, laboratory tests and operation information were collected. Patients were divided into a transfusion and a non-transfusion group. Different transfusion patterns were compared and analyzed. Results: Between the two groups, there is a significant difference in postoperative hemoglobin levels, and as well as gender, age, surgery duration, body weight change, intraoperative transfusion volume and blood loss, hospital length of stay, and surgical site distribution. There is a significant difference in the comparison of hospital stay length, autologous transfusion volume, combined allogeneic volume, operative blood loss, intraoperative transfusion volume, and change in hemoglobin levels between predonation and acute normovolemic hemodilution (ANH) transfusion. In comparison with the allogeneic transfusion-only patients, the mean allogeneic transfusion volume in either ANH group, predonated transfusion group, or mixed group is statistically lower. Allogeneic transfusion volume in the predonated-only group is significantly lower than that of either the ANH-only group or the mixing ANH with predonation group. Ordinary least squares regression analysis suggests that autologous transfusion in the ANH-only mode is statistically associated with allogeneic transfusion. Conclusions: This study described the blood transfusion in lymphedema liposuction surgery and compared autologous and allogeneic transfusion patterns in these patients. Autologous transfusion can reduce the transfusion volume of allogeneic blood and might be a beneficial mode of transfusion in these patients.

Population pharmacokinetics and exposure-response modeling analyses of guselkumab in patients with psoriatic arthritis.

Guselkumab is an anti-interleukin-23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure-response relationship of guselkumab in PsA, population PKs, and exposure-response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration-time data of guselkumab were adequately described by a one-compartment linear PK model with first-order absorption and elimination. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure-response relationships were demonstrated with landmark and longitudinal exposure-response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C-reactive protein level were identified as influencing covariates on guselkumab exposure-response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure-response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA.

Prevalence and intervention of preoperative anemia in Chinese adults: A retrospective cross-sectional study based on national preoperative anemia database.

BACKGROUND: Preoperative anemia is an important pillar of perioperative patient blood management. However, there was no literature comprehensively described the current situation of preoperative anemia in China. METHODS: We conducted a national retrospective cross-sectional study to assess the prevalence and intervention of preoperative anemia in Chinese adults. Data were from the National Preoperative Anemia Database based on hospital administration data from January 1, 2013 to December 31, 2018. FINDINGS: A total of 797,002 patients were included for analysis. Overall, 27.57% (95% CI 27.47-27.67) of patients had preoperative anemia, which varied by gender, age, regions, and type of operation. Patients who were female, age over 60 years old, from South China, from provinces with lower per capita GDP, underwent operations on the lymphatic and hematopoietic system, with laboratory abnormalities were more likely to have a high risk of preoperative anemia. Among patients with preoperative anemia, 5.16% (95% CI 5.07-5.26) received red blood cell transfusion, 7.79% (95% CI 7.67-7.91) received anemia-related medications such as iron, erythropoietin, folic acid or vitamin B12, and 12.25% (95% CI 12.10-12.40) received anemia-related therapy (red blood cell transfusion or anemia-related medications) before operation. The probability of preoperative RBC transfusion decreased by 54.92% (OR 0.46, 95% CI 0.46-0.47) as each 10-g/L increase in preoperative hemoglobin. Patients with preoperative hemoglobin less than 130 g/L was associated with longer hospital stay and more hospital costs. Patients with severe preoperative anemia given iron preoperatively had lower intra/post-operative RBC transfusion rate, shorter length of stay and less hospitalization costs, but no similar correlation was found in patients with mild and moderate preoperative anemia and patients given erythropoietin preoperatively. INTERPRETATION: Our present study shows that preoperative anemia is currently a relatively prevalent problem that has not been fully appreciated in China. More researches will be required to optimize the treatment of preoperative anemia. FUNDING: National Natural Science Foundation of China and the Logistics Support Department of the Central Military Commission.

Machine learning for predicting preoperative red blood cell demand.

BACKGROUND: The paucity of accurate quantitative standards for determining the quantity of red blood cells (RBCs) needed for perioperative patients and the predominant application of the "preoperative hemoglobin + surgery type" empirical decision-making model have led to widespread RBC application problems. OBJECTIVE: The mathematical model of preoperative variables constructed by machine learning (ML) methods can help doctors decide preoperative RBC applications. METHODS: We retrospectively analysed 130 996 records of patients who received surgery in our hospital from January 2011 to June 2017. Through the analysis of multiple preoperative parameters that may affect the RBC transfusion volume, we used ML algorithms to build up the artificial intelligence (AI) model to predict the accurate RBC demand quantity and compared each result with those predicted by clinicians. RESULTS: Among the seven ML algorithms, the light gradient boosting machine (Lightgbm) algorithm was the best. The AI model predicted whether the patients needed RBC transfusion, and the area under curve (AUC) was 0.908 (95% CI 0.907-0.913). The AI model was more accurate than doctors in predicting RBC of 0, 2, and 4 units (85% data), with RMSEs of 1.61 vs. 2.15, 1.06 vs. 1.21, and 1.46 vs. 1.68, respectively. However, the AI model was not better than doctors in 1, 3, 5-6, 7-8, and 9-10 units (15% data), with RMSEs of 0.92 vs. 0.89, 0.92 vs. 0.89, 2.73 vs. 1.94, 4.53 vs. 3.92, and 6.26 vs. 5.08, respectively. CONCLUSION: Through the comparison of seven ML methods, the Lightgbm algorithm-based model is more accurate than clinician experience-based in predicting preoperative RBC transfusion, which reduces the risk of untimely blood supply caused by insufficient preoperative blood preparation, and reduces the unnecessary cost of blood compatibility testing caused by excessive preoperative blood preparation.

Nucleation and growth dynamics of graphene grown by radio frequency plasma-enhanced chemical vapor deposition.

We investigated the nucleation and grain growth of graphene grown on Cu through radio frequency plasma-enhanced chemical vapor deposition (RF-PECVD) at different temperatures. A reasonable shielding method for the placement of copper was employed to achieve graphene by RF-PECVD. The nucleation and growth of graphene grains during PECVD were strongly temperature dependent. A high growth temperature facilitated the growth of polycrystalline graphene grains with a large size (~ 2 µm), whereas low temperature induced the formation of nanocrystalline grains. At a moderate temperature (790 to 850 °C), both nanocrystalline and micron-scale polycrystalline graphene grew simultaneously on Cu within 60 s with 50 W RF plasma power. As the growth time increased, the large graphene grains preferentially nucleated and grew rapidly, followed by the nucleation and growth of nanograins. There was competition between the growth of the two grain sizes. In addition, a model of graphene nucleation and grain growth during PECVD at different temperatures was established.

Development of a new genetic reference material system based on Saccharomyces cerevisiae cells.

As an important quality control link of molecular diagnosis, genetic reference materials (RMs) are widely used in various gene detection platforms such as mutation detection, gene quantification, and second generation sequencing. However, contamination, construction, and storage of existing genetic RMs still remain challenges. Here, we established a new genetic RM system based on Saccharomyces cerevisiae. We chose the non-small cell lung cancer (NSCLC) mutation hotspots in Kirsten rat sarcoma viral oncogene (KRAS) and epidermal growth factor receptor (EGFR), using clustered regularly interspaced short palindromic repeats and CRISPR-associated protein (CRISPR-Cas9) system-mediated gene editing technology, combined with the high homologous recombination efficiency of Saccharomyces cerevisiae. A single copy of the target gene was inserted into the yeast genome, and the inserted target gene was stably inherited with the passage of yeast cells. The copy number calculation for the target gene can replays by cell counting. The RM system was evaluated by sequence, copy number, stability, and homogeneity. In summary, the recombinant yeast cell line has ease of construction and screening, stable genetic characteristics, accurate copy number calculation, and convenient culture and preservation. Our findings may provide new ideas and directions for the research and industrialization of genetic RMs.

Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). METHODS: Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. RESULTS: In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. CONCLUSION: Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA.ClinicalTrials.gov number NCT02277444.

New insights into molecules and pathways of cancer metabolism and therapeutic implications.

Cancer cells are abnormal cells that can reproduce and regenerate rapidly. They are characterized by unlimited proliferation, transformation and migration, and can destroy normal cells. To meet the needs for cell proliferation and migration, tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells. Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells, including glucose, lipid, and amino acid metabolism. The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells. In this review, we report the unique metabolic alterations in tumor cells which occur through various signaling axes, and present various modalities available for cancer diagnosis and clinical therapy. We further provide suggestions for the development of anti-tumor therapeutic drugs.

Pharmacokinetics and Pharmacodynamics of JNJ-55920839, an Antibody Targeting Interferon α/ω, in Healthy Subjects and Subjects with Mild-to-Moderate Systemic Lupus Erythematosus.

BACKGROUND: The interferon (IFN) pathway has been correlated with clinical and serological markers of disease activity in patients with systemic lupus erythematosus (SLE). OBJECTIVE: The pharmacokinetics and pharmacodynamics of JNJ-55920839, a fully human immunoglobulin G1κ antibody targeting IFNα/ω, were investigated. METHODS: In a double-blind, first-in-human study, Part A enrolled 48 healthy adults who received a single dose of placebo/JNJ-55920839 between 0.3 and 15 mg/kg intravenous (IV) or at 1 mg/kg subcutaneous (SC). Part B enrolled 26 adults with SLE who received placebo or JNJ-55920839 10 mg/kg IV 6 times biweekly. Pharmacokinetic parameters were calculated by noncompartmental analysis (NCA) and estimated by nonlinear mixed-effects modeling. RESULTS: JNJ-55920839 pharmacokinetics following a single IV infusion exhibited a biphasic disposition in healthy subjects. Maximum plasma concentration (Cmax) and area under the concentration-time curve values increased dose-proportionally. Mean clearance (CL) after a single IV infusion ranged between 2.28 and 3.09 mL/kg/day. Absolute bioavailability after a single SC injection was ≥ 80.0%. Mean terminal elimination half-life (t1/2) was similar after IV (20.7 to 24.6 days) and SC administration (22.6 days). Steady state of JNJ-55920839 was achieved 6 weeks after multiple 10 mg/kg IV doses in subjects with SLE. Mean steady-state CL and t1/2 were 4.73 mL/kg/day and 14.8 days, respectively. A linear 2-compartment population pharmacokinetic model with 1st-order absorption and elimination adequately characterized the pharmacokinetics; parameters were consistent with NCA estimates. Higher CL was estimated in subjects with SLE compared with healthy subjects, after correcting for body weight. A trend of increased total IFNα/ω levels was observed after treatment with JNJ-55920839. CONCLUSION: Pharmacokinetic and pharmacodynamic analyses of the data from this study demonstrated that there was biphasic disposition in both healthy subjects and subjects with SLE, CL was faster in subjects with SLE, and increases in total IFNα/ω levels were observed in both healthy subjects and subjects with SLE after treatment with JNJ-55920839, thus further development is supported. The study is registered at ClinicalTrials.gov NCT02609789.