Publications by authors named "Jiajun Liu"

126 Publications

A clinical staging proposal of the disease course over time in non-severe patients with coronavirus disease 2019.

Sci Rep 2021 05 21;11(1):10681. Epub 2021 May 21.

Department of Infectious Diseases, The First Affiliated Hospital of Xiamen University, NO.55 Zhenhai Road, Xiamen, 361003, Fujian, China.

Information on the clinical staging of coronavirus disease 2019 (COVID-19) is still limited. This study aimed to propose a clinical staging proposal of the disease course in non-severe patients with COVID-19. In this retrospective study, 108 non-severe patients with COVID-19 were grouped according to the duration from symptoms onset to hospital admission: ≤ 1 week, > 1 to 2 weeks, > 2 to 3 weeks, > 3 to 5 weeks, respectively. The dynamic changes of clinical signs were profiled across the four groups. A clinical staging proposal of the disease course over time was proposed from the perspective of the interaction between the virus and host. The prodromal phase, characterized by pneumonia, significant lymphopenia, and slightly elevated inflammatory markers, occurred in the first week after symptoms onset. In the second week, all the hematological and inflammatory markers were at the peak or bottom. Meanwhile, progressive pneumonia as well as the secondary damage of other organs (e.g. cardiac damage, coagulopathy, etc.) was significant during this period, making the disease progress into the apparent manifestation phase. In the third week, the improvement of the majority of clinical signs accompanied by a relatively high degree of inflammatory response defined the remission phase. After 3 weeks, patients were in the convalescent phase, in which all the indicators were maintained at a relatively normal level. We concluded that the disease course over time in non-severe patients with COVID-19 could be divided into four phases: the prodromal phase (in the first week), the apparent manifestation phase (in the second week), the remission phase (in the third week), and the convalescent phase (after 3 weeks), respectively. In clinical practice, tailored therapies should be considered seriously in different stages of the disease course.
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http://dx.doi.org/10.1038/s41598-021-90111-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140110PMC
May 2021

Phase 2, Randomized, Placebo-Controlled Trial of Dapirolizumab Pegol in Patients with Moderate-to-Severe Active Systemic Lupus Erythematosus.

Rheumatology (Oxford) 2021 May 6. Epub 2021 May 6.

UCB Pharma, Monheim am Rhein, Germany.

Objective: To evaluate dose-response, efficacy and safety of dapirolizumab pegol (DZP) in patients with systemic lupus erythematosus (SLE).

Methods: Adults with moderately to severely active SLE (SLEDAI-2K score ≥6 and ≥1 BILAG A or ≥ 2 BILAG B domain scores), receiving stable corticosteroid (≤40 mg/day prednisone-equivalent), antimalarial, or immunosuppressant drugs were included. Patients with stable lupus nephritis (proteinuria ≤2 g/day) not receiving high-dose corticosteroids or cyclophosphamide were permitted entry. Randomized patients received placebo or intravenous DZP (6/24/45 mg/kg) and standard-of-care (SOC) treatment every 4 weeks to week 24, after which patients received only SOC to week 48. The primary objective was to establish a dose-response relationship based on week 24 BILAG-Based Composite Lupus Assessment (BICLA) responder rates.

Results: All DZP groups exhibited improvements in clinical and immunological outcomes vs placebo at week 24; however, BICLA responder rates did not fit pre-specified dose-response models (best-fitting model [Emax]: p= 0.07). Incidences of serious treatment-emergent adverse events across DZP groups were low and similar to placebo. Following DZP withdrawal, SLEDAI-2K, physician's global assessment (PGA), BILAG, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores stabilized; BICLA and SLE Responder Index (SRI-4) responder rates declined (likely due to interventions with disallowed escape medications), BILAG flares increased, and immunologic parameters returned towards baseline.

Conclusions: Although the primary objective was not met, DZP appeared to be well tolerated, and patients exhibited improvements across multiple clinical and immunological measures of disease activity after 24 weeks relative to placebo. The potential clinical benefit of DZP warrants further investigation.
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http://dx.doi.org/10.1093/rheumatology/keab381DOI Listing
May 2021

HDAC8 promotes daunorubicin resistance of human acute myeloid leukemia cells via regulation of IL-6 and IL-8.

Biol Chem 2021 Mar 17;402(4):461-468. Epub 2020 Dec 17.

Department of Hematology and Hematology, Institute of Sun Yat-sen University, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Avenue, Guangzhou510630, P. R. China.

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.
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http://dx.doi.org/10.1515/hsz-2020-0196DOI Listing
March 2021

A Three-Limb Teleoperated Robotic System with Foot Control for Flexible Endoscopic Surgery.

Ann Biomed Eng 2021 Apr 8. Epub 2021 Apr 8.

Robotics Research Center, School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.

Flexible endoscopy requires a lot of skill to manipulate both the endoscope and the associated instruments. In most robotic flexible endoscopic systems, the endoscope and instruments are controlled separately by two operators, which may result in communication errors and inefficient operation. Our solution is to enable the surgeon to control both the endoscope and the instruments. Here, we present a novel tele-operation robotic endoscopic system commanded by one operator using the continuous and simultaneous movements of their two hands and one foot. This 13-degree-of-freedom (DoF) system integrates a foot-controlled robotic flexible endoscope and two hand-controlled robotic endoscopic instruments, a robotic grasper and a robotic cauterizing hook. A dedicated foot-interface transfers the natural foot movements to the 4-DoF movements of the endoscope while two other commercial hand interfaces map the movements of the two hands to the two instruments individually. An ex-vivo experiment was carried out by six subjects without surgical experience, where the simultaneous control with foot and hands was compared with a sequential clutch-based hand control. The participants could successfully teleoperate the endoscope and the two instruments to cut the tissues at scattered target areas in a porcine stomach. Foot control yielded 43.7% faster task completion and required less mental effort as compared to the clutch-based hand control scheme, which proves the concept of three-limb tele-operation surgery and the developed flexible endoscopic system.
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http://dx.doi.org/10.1007/s10439-021-02766-3DOI Listing
April 2021

Functional characterization of Fur in iron metabolism, oxidative stress resistance and virulence of Riemerella anatipestifer.

Vet Res 2021 Mar 19;52(1):48. Epub 2021 Mar 19.

Institute of Preventive Veterinary Medicine, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, 611130, Sichuan, China.

Iron is essential for most bacteria to survive, but excessive iron leads to damage by the Fenton reaction. Therefore, the concentration of intracellular free iron must be strictly controlled in bacteria. Riemerella anatipestifer (R. anatipestifer), a Gram-negative bacterium, encodes the iron uptake system. However, the iron homeostasis mechanism remains largely unknown. In this study, it was shown that compared with the wild type R. anatipestifer CH-1, R. anatipestifer CH-1Δfur was more sensitive to streptonigrin, and this effect was alleviated when the bacteria were cultured in iron-depleted medium, suggesting that the fur mutant led to excess iron accumulation inside cells. Similarly, compared with R. anatipestifer CH-1∆recA, R. anatipestifer CH-1∆recAΔfur was more sensitive to HO-induced oxidative stress when the bacteria were grown in iron-rich medium rather than iron-depleted medium. Accordingly, it was shown that R. anatipestifer CH-1∆recAΔfur produced more intracellular ROS than R. anatipestifer CH-1∆recA in iron-rich medium. Electrophoretic mobility shift assays showed that R. anatipestifer CH-1 Fur suppressed the transcription of putative iron uptake genes through binding to their promoter regions. Finally, it was shown that compared with the wild type, R. anatipestifer CH-1Δfur was significantly attenuated in ducklings and that the colonization ability of R. anatipestifer CH-1Δfur in various tissues or organs was decreased. All these results suggested that Fur is important for iron homeostasis in R. anatipestifer and its pathogenic mechanism.
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http://dx.doi.org/10.1186/s13567-021-00919-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976709PMC
March 2021

Antimicrobial never events: Objective application of a framework to assess vancomycin appropriateness.

Infect Control Hosp Epidemiol 2020 Dec 29:1-3. Epub 2020 Dec 29.

Midwestern University, Downers Grove, Illinois.

To address appropriateness of antibiotic use, we implemented an electronic framework to evaluate antibiotic "never events" (NEs) at 2 medical centers. Patient-level vancomycin administration records were classified as NEs or non-NEs. The objective framework allowed capture of true-positive vancomycin NEs in one-third of patients identified by the electronic strategy.
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http://dx.doi.org/10.1017/ice.2020.1350DOI Listing
December 2020

OsmiR164-targeted OsNAM, a boundary gene, plays important roles in rice leaf and panicle development.

Plant J 2021 Apr 1;106(1):41-55. Epub 2021 Feb 1.

College of Agriculture, Nanjing Agricultural University, Nanjing, 210095, People's Republic of China.

The CUP-SHAPED COTYLEDON (CUC) genes (CUC1, CUC2 and CUC3) regulate organ boundary formation in Arabidopsis. However, the functions of their homologous genes in rice (Oryza sativa) are still unknown. Here, we have identified an orthologous gene of CUC1 and CUC2 in rice, named OsNAM. Subcellular localization and yeast two-hybrid assay results have suggested that OsNAM encodes a conserved nuclear NAC (NAM/ATAF1/CUC2) protein with a transcriptional activator. The null mutant osnam-1 presented a fused leaf structure, small panicles, reduced branches and aberrant floral organ identities when compared with those of the wild type. Beta-glucuronidase staining and GFP reporter lines indicated that OsNAM was expressed in young tissues and that its boundary enrichment expression was regulated by OsmiR164. Loss-of-function mutants for OsCUC3 resulted in no obvious defects throughout rice development. The osnam oscuc3 double mutant, however, resulted in severe leaf fusion of the first two leaves, while the osnam single mutant showed a similar phenotype from the seventh leaf. These results indicated that OsNAM and OsCUC3 act redundantly for boundary specification during post-embryonic development. Overall, we describe the biological functions of OsNAM and OsCUC3 in rice development and the expression characteristics of OsNAM. This work reveals the important role of CUC genes in rice.
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http://dx.doi.org/10.1111/tpj.15143DOI Listing
April 2021

Vancomycin Exposure and Acute Kidney Injury Outcome: A Snapshot From the CAMERA2 Study.

Open Forum Infect Dis 2020 Dec 4;7(12):ofaa538. Epub 2020 Nov 4.

Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois, USA.

Among patients with methicillin-resistant (MRSA) bacteremia from a prospective randomized clinical trial, acute kidney injury (AKI) rates increased with increasing vancomycin exposure, even within the therapeutic range. AKI was independently more common for the (flu)cloxacillin group. Day 2 vancomycin AUC ≥470 mg·h/L was significantly associated with AKI, independent of (flu)cloxacillin receipt.
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http://dx.doi.org/10.1093/ofid/ofaa538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731530PMC
December 2020

The Pharmacodynamic-Toxicodynamic Relationship of AUC and in Vancomycin-Induced Kidney Injury in an Animal Model.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA

Vancomycin induces exposure-related acute kidney injury. However, the pharmacokinetic-toxicodynamic (PK-TD) relationship remains unclear. Sprague-Dawley rats received intravenous (i.v.) vancomycin doses of 300 mg/kg/day and 400 mg/kg/day, divided into once-, twice-, three-times-, or four-times-daily doses (i.e., QD, BID, TID, or QID) over 24 h. Up to 8 samples plus a terminal sample were drawn during the 24-h dosing period. Twenty-four-hour urine was collected and assayed for kidney injury molecule-1 (KIM-1). Vancomycin was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Following terminal sampling, nephrectomy and histopathologic analyses were conducted. PK analyses were conducted using Pmetrics. PK exposures (i.e., area under the concentration-time curve from 0 to 24 h [AUC] and maximum concentration from 0 to 24 h []) were calculated for each rat, and PK-TD relationships were discerned. A total of 53-rats generated PK-TD data. A 2-compartment model fit the data well (Bayesian observed versus predicted concentrations; = 0.96). KIM-1 values were greater in QD and BID groups ( for QD versus TID, <0.002; for QD versus QID, <0.004; for BID versus TID, <0.002; and for BID versus QID, <0.004). Exposure-response relationships were observed between KIM-1 versus and AUC ( = 0.7 and 0.68). Corrected Akaike's information criterion showed as the most predictive PK-TD driver for vancomycin-induced kidney injury (VIKI) (-5.28 versus -1.95). While PK-TD indices are often intercorrelated, maximal concentrations and fewer doses (for the same total daily amount) resulted in increased VIKI in our rat model.
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http://dx.doi.org/10.1128/AAC.01945-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092494PMC
February 2021

Vancomycin Duration Therapy.

Clin Infect Dis 2020 Dec 13. Epub 2020 Dec 13.

Department of Pharmacy Practice, Midwestern University College of Pharmacy, Downers Grove, IL, USA.

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http://dx.doi.org/10.1093/cid/ciaa1849DOI Listing
December 2020

Highly Penetrable and On-Demand Oxygen Release with Tumor Activity Composite Nanosystem for Photothermal/Photodynamic Synergetic Therapy.

ACS Nano 2020 Dec 8. Epub 2020 Dec 8.

Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.

A deep penetrating and pH-responsive composite nanosystem was strategically developed to improve the efficacy of synergetic photothermal/photodynamic therapy (PTT/PDT) against hypoxic tumor. The designed nanosystem ([PHC][email protected] NPs) was constructed by coloading hemoglobin (Hb) and chlorin e6 on polydopamine to build small-sized PHC NPs, which were encapsulated inside the polymer micelles (poly(ethylene glycol)-poly(ethylenimine)) and then capped with functionalized hyaluronic acid. The pH-responsive feature made [PHC][email protected] NPs retain an initial size of ∼140 nm in blood circulation but rapidly release small PHC NPs (∼10 nm) with a high tumor-penetrating ability in the tumor microenvironment. The penetration experiment showed that the penetration depth of PHC NPs in the multicellular tumor spheroids exceeded 110 μm. The [PHC][email protected] NPs exhibited excellent biocompatibility, deep tumor permeability, high photothermal conversion efficiency (47.09%), and low combination index (0.59) under hypoxic conditions. Notably, the nanosystem can freely adjust the release of oxygen and damaging PHC NPs in an on-demand manner on the basis of the feedback of tumor activity. This feedback tumor therapy significantly improved the synergistic effect of PTT/PDT and reduced its toxic side effects. The antitumor results showed that the tumor inhibition rate of [PHC][email protected] NPs with an on-demand oxygen supply of Hb was ∼100%, which was much better than those of PTT alone and Hb-free nanoparticles ([PC][email protected] NPs). Consequently, the [PHC][email protected] NP-mediated PTT/PDT guided by feedback tumor therapy achieved an efficient tumor ablation with an extremely low tumor recurrence rate (8.3%) 60 d later, indicating the versatile potential of PTT/PDT.
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http://dx.doi.org/10.1021/acsnano.0c06415DOI Listing
December 2020

Graded peripheral nerve injury creates mechanical allodynia proportional to the progression and severity of microglial activity within the spinal cord of male mice.

Brain Behav Immun 2021 01 13;91:568-577. Epub 2020 Nov 13.

Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics (WNLO), Huazhong University of Science and Technology (HUST), Wuhan, Hubei, PR China; School of Biomedical Engineering, Hainan University, Haikou, Hainan 570228, PR China. Electronic address:

The reactivity of microglia within the spinal cord in response to nerve injury, has been associated with the development and maintenance of neuropathic pain. However, the temporal changes in microglial reactivity following nerve injury remains to be defined. Importantly, the magnitude of behavioural allodynia displayed and the relationship to the phenotypic microglial changes is also unexplored. Using a heterozygous CXCR transgenic mouse strain, we monitored microglial activity as measured by cell density, morphology, process movement and process length over 14 days following chronic constriction of the sciatic nerve via in vivo confocal microscopy. Uniquely this relationship was explored in groups of male mice which had graded nerve injury and associated graded behavioural mechanical nociceptive sensitivity. Significant mechanical allodynia was quantified from the ipsilateral hind paw and this interacted with the extent of nerve injury from day 5 to day 14 (p < 0.009). The extent of this ipsilateral allodynia was proportional to the nerve injury from day 5 to 14 (Spearman rho = -0.58 to -0.77; p < 0.002). This approach allowed for the assessment of the association of spinal microglial changes with the magnitude of the mechanical sensitivity quantified behaviourally. Additionally, the haemodynamic response in the somatosensory cortex was quantified as a surrogate measure of neuronal activity. We found that spinal dorsal horn microglia underwent changes unilateral to the injury in density (Spearman rho = 0.47; p = 0.01), velocity (Spearman rho = -0.68; p = 0.00009), and circularity (Spearman rho = 0.55; p = 0.01) proportional to the degree of the neuronal injury. Importantly, these data demonstrate for the first time that the mechanical allodynia behaviour is not a binary all or nothing state, and that microglial reactivity change proportional to this behavioural measurement. Increased total haemoglobin levels in the somatosensory cortex of higher-grade injured animals was observed when compared to sham controls suggesting increased neuronal activity in this brain region. The degree of phenotypic microglial changes quantified here, may explain how microglia can induce both rapid onset and sustained functional changes in the spinal cord dorsal horn, following peripheral injury.
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http://dx.doi.org/10.1016/j.bbi.2020.11.018DOI Listing
January 2021

Generation of a RGS18 gene knockout cell line from a human embryonic stem cell line by CRISPR/Cas9.

Stem Cell Res 2020 12 29;49:102072. Epub 2020 Oct 29.

Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address:

RGS18 is a member of the RGS (Regulators of G-protein signaling) protein family, involved in megakaryopoiesis, megakaryocyte differentiation and chemotaxis. Here, we created a RGS18 knockout cell line from a human embryonic stem cell line by CRISPR/Cas9 mediated gene targeting, to further understand roles of RGS18 in these processes. The cell line maintains stem cell morphology and normal karyotype, and retains expression of pluripotent marker genes and differentiation potential in vivo. The RGS18 cell line will facilitate investigation of the role of RGS18 during multiple cellular processes in human pluripotent stem cell modeled hematopoiesis.
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http://dx.doi.org/10.1016/j.scr.2020.102072DOI Listing
December 2020

Performance of F-FDG PET/CT Radiomics for Predicting EGFR Mutation Status in Patients With Non-Small Cell Lung Cancer.

Front Oncol 2020 8;10:568857. Epub 2020 Oct 8.

Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: To assess the performance of pretreatment F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) radiomics features for predicting EGFR mutation status in patients with non-small cell lung cancer (NSCLC).

Patients And Methods: We enrolled total 173 patients with histologically proven NSCLC who underwent preoperative F-FDG PET/CT. Tumor tissues of all patients were tested for EGFR mutation status. A PET/CT radiomics prediction model was established through multi-step feature selection. The predictive performances of radiomics model, clinical features and conventional PET-derived semi-quantitative parameters were compared using receiver operating curves (ROCs) analysis.

Results: Four CT and two PET radiomics features were finally selected to build the PET/CT radiomics model. Compared with area under the ROC curve (AUC) equal to 0.664, 0.683 and 0.662 for clinical features, maximum standardized uptake values (SUV) and total lesion glycolysis (TLG), the PET/CT radiomics model showed better performance to discriminate between EGFR positive and negative mutations with the AUC of 0.769 and the accuracy of 67.06% after 10-fold cross-validation. The combined model, based on the PET/CT radiomics and clinical feature (gender) further improved the AUC to 0.827 and the accuracy to 75.29%. Only one PET radiomics feature demonstrated significant but low predictive ability (AUC = 0.661) for differentiating 19 Del from 21 L858R mutation subtypes.

Conclusions: EGFR mutations status in patients with NSCLC could be well predicted by the combined model based on F-FDG PET/CT radiomics and clinical feature, providing an alternative useful method for the selection of targeted therapy.
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http://dx.doi.org/10.3389/fonc.2020.568857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578399PMC
October 2020

IL-8/CXCR2 mediates tropism of human bone marrow-derived mesenchymal stem cells toward CD133 /CD44 Colon cancer stem cells.

J Cell Physiol 2021 Apr 20;236(4):3114-3128. Epub 2020 Oct 20.

State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.

In cancer treatment, the most attractive feature of mesenchymal stem cells (MSCs) is it's homing to tumor tissues. MSC is an important part of the "colon cancer stem cell niche", but little research has been done on the tropism of human MSCs toward colon cancer stem cells (CCSCs). In this study, we first compared the effects of three tissue-derived MSCs (bone marrow, adipose tissue, and placenta) in vivo on colon tumor xenograft growth. Then, we analyzed the tropism of bone marrow-derived MSCs (BMSCs) toward normal intestinal epithelial cells (NCM460), parental colon cancer cells, CD133 /CD44 and CD133 /CD44 colon cancer cells in vitro. Microarray analysis and in vitro experiments explored the mechanism of mediating the homing of BMSCs toward CCSCs. Compared with the parental and CD133 /CD44 colon cancer cells, CD133 /CD44 cells have a stronger ability to recruit BMSCs. In addition, BMSCs were significantly transformed into cancer-associated fibroblasts after being recruited by CCSCs. After coculture of BMSCs and CCSCs, the expression of interleukin (IL)-6, IL-8, IL-32, and CCL20 was significantly increased. Compared with parental strains, CD133 /CD44 cells, and NCM460, BMSC secreted significantly more IL-8 after coculture with CD133 /CD44 cells. Low concentration of IL-8 peptide inhibitors (100 ng/ml) and CXC receptor 2 (CXCR2) inhibitors have little effect on the migration of BMSCs, but can effectively weaken CCSC stemness and promote dormant CSCs in the coculture system to re-enter into the cell cycle. The endogenous IL-8 knockout in BMSCs or BMSCs loaded with IL-8 and/or CXCR2 inhibitors will make the therapy of BMSC targeting CCSCs function at its best.
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http://dx.doi.org/10.1002/jcp.30080DOI Listing
April 2021

QTL mapping and validation of bread wheat flag leaf morphology across multiple environments in different genetic backgrounds.

Theor Appl Genet 2021 Jan 7;134(1):261-278. Epub 2020 Oct 7.

State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Triticeae Research Institute, Sichuan Agricultural University, Chengdu, 611130, China.

Key Message: Eight major and stably expressed QTL for flag leaf morphology across eleven environments were identified and validated using newly developed KASP markers in seven biparental populations with different genetic backgrounds. Flag leaf morphology is a determinant trait influencing plant architecture and yield potential in wheat (Triticum aestivum L.). A recombinant inbred line (RIL) population with a 55 K SNP-based constructed genetic map was used to map quantitative trait loci (QTL) for flag leaf length (FLL), width (FLW), area (FLA), angle (FLANG), opening angle (FLOA), and bend angle (FLBA) in eleven environments. Eight major QTL were detected in 11 environments with 5.73-54.38% of explained phenotypic variation. These QTL were successfully verified using the newly developed Kompetitive Allele Specific PCR (KASP) markers in six biparental populations with different genetic backgrounds. Among these 8 major QTL, two co-located intervals were identified. Significant interactions for both FLL- and FLW-related QTL were detected. Comparison analysis showed that QFll.sau-SY-2B and QFla.sau-SY-2B are likely new loci. Significant relationships between flag leaf- and yield-related traits were observed and discussed. Several genes associated with leaf development including the ortholog of maize ZmRAVL1, a B3-domain transcription factor involved in regulation of leaf angle, were predicted in physical intervals harboring these major QTL on reference genomes of bread wheat 'Chinese spring', T. turgidum, and Aegilops tauschii. Taken together, these results broaden our understanding on genetic basis of flag leaf morphology and provide clues for fine mapping and marker-assisted breeding wheat with optimized plant architecture for promising loci.
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http://dx.doi.org/10.1007/s00122-020-03695-wDOI Listing
January 2021

Esophageal squamous cell cancer coincides with myelodysplastic syndrome/acute myelogenous leukemia: A case report and review of the literature.

Oncol Lett 2020 Nov 21;20(5):266. Epub 2020 Sep 21.

Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University and Sun Yat-Sen Institute of Hematology, Guangzhou, Guangdong 510630, P.R. China.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, and has high incidence and mortality rates, worldwide. Myelodysplastic syndrome (MDS), a disorder of hematopoietic stem or progenitor cells, results in marrow failure, which increases the risk of acute myeloid leukemia (AML). Few studies had reported patients who have suffered from both ESCC and MDS/AML simultaneously. To identify possible potential associations between ESCC and MDS/AML, the present case report describes a patient with both types of these tumors at the same time. Following endoscopic biopsy, the patient was revealed to have moderately differentiated SCC. MDS with excess blasts was subsequently diagnosed following bone marrow aspiration. The results of next-generation sequencing revealed that TP53 and ROS1 were both found in ESCC and MDS/AML tumors. The patient refused therapeutic intervention and died within 20 days. The current report demonstrated that hematologic malignancies presenting alongside solid tumors should be considered clinically. In addition, the report indicated that bone marrow puncture should be performed in patients with solid tumors and abnormal blood test results. Next-generation sequencing may be a useful technique for the investigation of patients with two or more neoplasms. However, more research regarding the co-existence of solid tumors with hematological malignancy are required.
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http://dx.doi.org/10.3892/ol.2020.12129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517598PMC
November 2020

β-lactam dosing strategies: Think before you push.

Int J Antimicrob Agents 2020 Nov 31;56(5):106151. Epub 2020 Aug 31.

Midwestern University Chicago College of Pharmacy, Downers Grove, USA; Northwestern Memorial Hospital, Chicago, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, USA. Electronic address:

Objectives: There has been interest in administering cefepime, a β-lactam antibiotic, via intravenous push (IVP) as a means to improve time to first-dose antibiotic and reduce cost; however, the downstream impacts on antibiotic exposure and pharmacodynamic efficacy need to be further evaluated.

Methods: This study used a population pharmacokinetic model for cefepime and simulated exposures to predict the pharmacodynamic (PD) effect for cefepime regimens administered via IVP or 30-minute intermittent infusion in adults with different renal functions. FDA-approved adult dosages of 1-2 g every 8 or 12 hours were compared. This study aimed to compare the absolute difference in pharmacodynamic probability of target attainment (PTA) between IVP and intermittent infusion, defined as free cefepime concentrations above organism MIC for ≥ 70% of the time.

Results: At MICs of 0.25-0.5 mg/L, absolute differences in PTA were observed, with a reduction as great as 2.3% (89% to 86.7% for 30-minute intermittent infusion and IVP, respectively). At MICs of 1-4 mg/L, 30-minute intermittent infusion and IVP exhibited PTA differences as great as 5.4%, from 89.4% to 84%, respectively. At MICs of ≥8 mg/L, similar absolute differences existed; however, no regimen achieved a PTA >70%. Across renal function strata of 60, 100 and 140 mL/minute (within the same dosing group and MICs), better renal function lowered PTAs.

Conclusions: Simulations demonstrated that IVP cefepime resulted in lower PTAs than traditional intermittent infusion among a subset of elevated MICs. Clinicians should exercise caution in IVP strategy, as unintended clinical consequences are possible.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106151DOI Listing
November 2020

Identification and Validation of an Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction.

Cancers (Basel) 2020 Aug 8;12(8). Epub 2020 Aug 8.

Departments of Molecular Biosciences, the University of Kansas, Lawrence, KS 66045, USA.

RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include , , and , key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1-mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from . One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology.
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http://dx.doi.org/10.3390/cancers12082221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463734PMC
August 2020

A novel, major, and validated QTL for the effective tiller number located on chromosome arm 1BL in bread wheat.

Plant Mol Biol 2020 Sep 30;104(1-2):173-185. Epub 2020 Jul 30.

State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Triticeae Research Institute, Sichuan Agricultural University, Chengdu, 611130, China.

Key Message: A novel and major QTL for the effective tiller number was identified on chromosomal arm 1BL and validated in two genetic backgrounds The effective tiller number (ETN) substantially influences plant architecture and the wheat yield improvement. In this study, we constructed a genetic map of the 2SY (20828/SY95-71) recombinant inbred line population based on the Wheat 55K array as well as the simple sequence repeat (SSR) and Kompetitive Allele Specific PCR (KASP) markers. A comparison between the genetic and physical maps indicated the marker positions were consistent in the two maps. Additionally, we identified seven tillering-related quantitative trait locus (QTLs), including Qetn-sau-1B.1, which is a major QTL localized to a 6.17-cM interval flanked by markers AX-89635557 and AX-111544678 on chromosome 1BL. The Qetn-sau-1B.1 QTL was detected in eight environments and explained 12.12-55.71% of the phenotypic variance. Three genes associated with the ETN were detected in the physical interval of Qetn-sau-1B.1. We used a tightly linked KASP marker, KASP-AX-110129912, to further validate this QTL in two other populations with different genetic backgrounds. The results indicated that Qetn-sau-1B.1 significantly increased the ETN by up to 23.5%. The results of this study will be useful for the precise mapping and cloning of Qetn-sau-1B.1.
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http://dx.doi.org/10.1007/s11103-020-01035-6DOI Listing
September 2020

Is There an Association Between Contraception and Sexual Dysfunction in Women? A Systematic Review and Meta-analysis Based on Female Sexual Function Index.

J Sex Med 2020 10 18;17(10):1942-1955. Epub 2020 Jul 18.

Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong, China. Electronic address:

Background: A growing body of research investigates the sexual functioning status in women with contraceptives use; however, the evidence is still inconclusive.

Aim: To examine whether contraceptives use is associated with a higher risk of female sexual dysfunction (FSD).

Methods: The electronic databases MEDLINE, Embase, Cochrane Library databases, and PsychINFO were systematically screened for eligible studies before December 2019. We only included those studies assessing women's sexual functioning by the Female Sexual Function Index (FSFI). This study was registered on the PROSPERO (ID: CRD42020167723, http://www.crd.york.ac.uk/PROSPERO).

Outcomes: The strength of the association between contraceptives use and risk of FSD was presented by calculating the standard mean dierences (SMDs) and the relative risk (RR) with a 95% confidence interval (CI). The pooled results were calculated using a random-effects model.

Results: A total of 12 studies (7 cross-sectional studies, 3 cohorts, and 1 case-control study) involving 9,427 participants were included. The mean age in the contraceptive users ranged from 22.5 ± 2.4 years to 38.2 ± 4.6 years, while the mean age in the nonusers was 22.5 ± 2.4 years to 36.0 ± 1.0 years. Pooled results showed that no significant difference in the total FSFI scores was observed between contraceptives use and noncontraception (SMD = -1.03, 95% CI: -2.08 to 0.01, P = .053; heterogeneity: I = 98.2%, P < .001). In line with this finding, the pooled RR also yielded no association between contraception use and the risk of FSD (RR = 1.29, 95% CI: 0.72-2.28, P = .392; heterogeneity: I = 76.0%, P = .0015). However, the subscale sexual desire showed a significant reduction in women who received contraceptives than those did not use contraception (SMD = -1.17, 95% CI: -2.09 to -0.24, P = .014; heterogeneity: I = 97.7%, P < .001), while no significant differences were found in sexual arousal, lubrication, orgasm, satisfaction, and pain domain.

Clinical Implications: Though evidence from this meta-analysis did not support an association between contraceptives use and the risk of FSD, the sexual desire could be significantly impaired by contraceptives use.

Strengths & Limitations: This is the first meta-analysis quantifying the relationship between contraceptives use and the risks of FSD. However, substantial heterogeneities were presented across the included studies.

Conclusion: No direct association between contraceptives use and the risk of FSD was found. Nevertheless, declining sexual desire was significantly associated with contraceptives use. Additional double-blind, randomized, placebo-controlled trials are still warranted. Huang M, Li G, Liu J, et al. Is There an Association Between Contraception and Sexual Dysfunction in Women? A Systematic Review and Meta-analysis Based on Female Sexual Function Index. J Sex Med 2020;17:1942-1955.
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http://dx.doi.org/10.1016/j.jsxm.2020.06.008DOI Listing
October 2020

Author Correction: EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance.

Nat Commun 2020 07 16;11(1):3655. Epub 2020 Jul 16.

Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-17430-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366623PMC
July 2020

Population Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial Dosing.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Infectious Disease Pharmacokinetics Laboratory, Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA

Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC (T) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a prospective study of pediatric patients who received cefepime at 50 mg/kg of body weight and had extensive PK sampling. The second study comprised retrospective data for adult ICU patients admitted to UF Health Shands Hospital who received cefepime and had their cefepime concentrations measured. The population PK model was developed, and simulations were performed, using Pmetrics. The target exposures were 100% T and 100% T The studies included a total of 266 patients, and the mean ages were 3.9 years in the pediatric group and 55 years in adult group. More than half of the patients were males. The mean (standard deviation [SD]) creatinine clearance (CrCl) was 125 (93) ml/min. The mean (SD) daily dose for adults was 4.9 (1.6) g. Cefepime was well described by a two-compartment model with weight as a covariate on the volume of distribution and elimination rate constant (), and CrCl and age group as covariates on At a MIC of 8 mg/liter, a cefepime loading dose of 4 g as an extended infusion followed by a 6-g continuous infusion was needed for good target attainment. In conclusion, prolonged or continuous infusions will be needed to achieve optimal cefepime exposure for ICU patients. Given the observed variability, therapeutic drug monitoring can help individualize therapy.
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http://dx.doi.org/10.1128/AAC.00745-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449216PMC
August 2020

PGcloser: Fast Parallel Gap-Closing Tool Using Long-Reads or Contigs to Fill Gaps in Genomes.

Evol Bioinform Online 2020 23;16:1176934320913859. Epub 2020 Apr 23.

China Tobacco Gene Research Center, Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou, China.

Assembled draft genomes usually contain many gaps because of the length limit of next-generation sequencing. Although many gap-closing tools have been developed, most of them still attempt to fill gaps on the basis of next-generation sequencing reads (always < 200 bp). Hence, the gap-filling effect is inferior. Several tools that use long-reads to close gaps have recently been created. However, they require extensive runtimes, which may not be suitable for large genomes. We describe a gap-closing tool called PGcloser, which supports parallel mode and adopts long-reads/contigs to fill gaps in genome sequences. Three tests show that PGcloser is faster than other tools but exhibits similar accuracy. PGcloser is free open-source software that is available at http://software.tobaccodb.org/software/pgcloser.
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http://dx.doi.org/10.1177/1176934320913859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180314PMC
April 2020

Gene coexpression network analysis revealed biomarkers correlated with blast cells and survival in acute myeloid leukemia.

Mol Clin Oncol 2020 May 26;12(5):475-484. Epub 2020 Feb 26.

Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China.

Acute myeloid leukemia (AML) is a hematological malignancy with a poorly understood pathogenesis, especially among patients with no known cytogenetic abnormalities. Furthermore, there is a lack of therapeutic gene targets and diagnostic biomarkers for the effective treatment of AML. The present study aimed to identify candidate biomarkers correlated with the clinical prognosis of patients with AML. Leukemic cells from 5 patients with AML exhibiting a normal karyotype, and hematopoietic cells from 5 healthy donors were processed for RNA sequencing (RNA-seq), and the obtained RNA expression profiles were subjected to weighted gene correlation network analysis. A novel group of genes (the red module) were identified to be significantly associated with AML, and this module contained a closely connected network with 147 nodes, which corresponded to 114 mRNAs. Analysis of the correlation between these mRNAs and blast cell percentage, overall survival (OS) and disease-free survival (DFS) using cases from The Cancer Genome Atlas (TCGA) database revealed that , and were negatively associated with the percentage of blast cells, while high expression of these genes was associated with longer OS and DFS in patients with AML. The differential expression of these three genes between patients with AML and healthy control subjects was supported using the Genotype-Tissue Expression and TCGA databases and was further confirmed using reverse transcription-quantitative (RT-qPCR). These genes exhibited significantly lower expression in patients with AML compared with control subjects. The results indicated that , and exhibit the potential to be prognostic biomarkers. However, the biological functions of these three candidate genes need to be assessed in further studies.
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http://dx.doi.org/10.3892/mco.2020.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087465PMC
May 2020

Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention.

Pharmacotherapy 2020 05 4;40(5):438-454. Epub 2020 May 4.

Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois.

Vancomycin is a recommended therapy in multiple national guidelines. Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin-mediated kidney injury. In this review, historic and contemporary rates of vancomycin-induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge that may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.
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http://dx.doi.org/10.1002/phar.2388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331087PMC
May 2020

A Temperature-Dependent, Variable-Stiffness Endoscopic Robotic Manipulator with Active Heating and Cooling.

Ann Biomed Eng 2020 Jun 30;48(6):1837-1849. Epub 2020 Mar 30.

Robotics Research Center, School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.

In flexible endoscopy, the endoscope needs to be sufficiently flexible to go through the tortuous paths inside the human body and meanwhile be stiff enough to withstand external payloads without unwanted tip bending during operation. Thus, an endoscope whose stiffness can be adjusted on command is needed. This paper presents a novel variable-stiffness manipulator. The manipulator (Ø15 mm) has embedded thermoplastic tubes whose stiffness is tunable through temperature. Temperature is adjusted through joule heat generated by the electrical current supplied to the stainless steel coils and an active air-cooling mechanism. Tests and modeling were conducted to characterize the performance of the design. The manipulator has a high stiffness-changing ratio (22) between rigid and flexible states while that of its commercial Olympus counterpart is only 1.59. The active cooling time is 11.9 s while that of passive ambient cooling is 100.3 s. The thermal insulation layer (Aerogel) keeps the temperature of the outer surface within the safe range (below 41 °C). The models can describe the heating and cooling processes with root mean square errors ranging from 0.6 to 1.3 °C. The results confirm the feasibility of a variable-stiffness endoscopic manipulator with high stiffness-changing ratio, fast mode-switching, and safe thermal insulation.
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http://dx.doi.org/10.1007/s10439-020-02495-zDOI Listing
June 2020

Dihydroartemisinin Ameliorates Learning and Memory in Alzheimer's Disease Through Promoting Autophagosome-Lysosome Fusion and Autolysosomal Degradation for Aβ Clearance.

Front Aging Neurosci 2020 2;12:47. Epub 2020 Mar 2.

Neuroscience Research Center, Chongqing Medical University, Chongqing, China.

Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer's disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model and . Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD.
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http://dx.doi.org/10.3389/fnagi.2020.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067048PMC
March 2020

Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea.

J Pain Res 2020 9;13:503-516. Epub 2020 Mar 9.

School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC).

Patients And Methods: Fifty-six women aged 16-35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL-1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs.

Results: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI -4.69, -0.09) increase in IL-1β release when compared with pain-free participants across both days.

Conclusion: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.
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http://dx.doi.org/10.2147/JPR.S219684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071941PMC
March 2020

Development of Population and Bayesian Models for Applied Use in Patients Receiving Cefepime.

Clin Pharmacokinet 2020 08;59(8):1027-1036

Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL, 60515, USA.

Background And Objective: Understanding pharmacokinetic disposition of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment.

Methods: Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of 12 pediatric patients and two separate adult populations were assessed.

Results: Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n = 34) on average weighed 82.7 kg and displayed a mean creatinine clearance of 106.7 mL/min. All pediatric subjects (n = 36) had mean weight and creatinine clearance of 16.0 kg and 195.6 mL/min, respectively. A covariate-adjusted two-compartment model described the observed concentrations well (population model R, 87.0%; Bayesian model R, 96.5%). In the evaluation subsets, the model performed similarly well (population R, 84.0%; Bayesian R, 90.2%).

Conclusion: The identified model serves well for population dosing and as a Bayesian prior for precision dosing.
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http://dx.doi.org/10.1007/s40262-020-00873-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222999PMC
August 2020