Publications by authors named "Wei Fu"

586 Publications

The effect of Guanxin Shutong capsule on alleviating the myocardial fibrosis in heart failure rats.

J Ethnopharmacol 2021 Apr 28:114169. Epub 2021 Apr 28.

Zhejiang Chinese Medical University, Hangzhou, 310053, China. Electronic address:

Ethnopharmacological Relevance: Guanxin Shutong (GXST) capsule is a renowned traditional Chinese medicine widely used for the treatment of cardiovascular diseases in the clinic. However, no pharmacological experimental studies of GXST has been reported on the treatment of pressure overload-induced heart failure. This study aimed to investigate the effects of GXST capsule on ameliorating myocardial fibrosis conditions in pressure overload-induced heart failure rats.

Material And Methods: Rats were randomly divided into 6 groups: Normal group, Model group, GXST-treated group at a dose of 0.5 g/kg, 1 g/kg, 2 g/kg, respectively, and digoxin positive control group at a dose of 1 mg/kg. After 4 weeks of administration, cardiac function was evaluated by echocardiography. Cardiac injury and fibrotic conditions were evaluated by H&E staining, Masson staining, and Sirius Red staining. Myocardial fibrosis was evaluated by immunohistochemistry staining and western blot.

Results: GXST significantly inhibited cardiac fibrosis, reduced the excessive deposition of collagen, and finally improved cardiac function. GXST reversed ventricular remodeling might be through the TGF-β/Smad3 pathway.

Conclusion: GXST capsule demonstrated a strong anti-fibrosis effect in heart failure rats by inhibiting the TGF-β/Smad3 signaling pathway.
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http://dx.doi.org/10.1016/j.jep.2021.114169DOI Listing
April 2021

Bone density and fracture risk following SBRT for non-spine bone metastases.

J Radiosurg SBRT 2021 ;7(3):199-206

Johns Hopkins University School of Medicine, Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, MD, USA.

Purpose/methods: This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT.

Results: 181 lesions in 116 patients are reported. The median dose was 27 Gy (range 15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units).

Conclusion: In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055232PMC
January 2021

Acylphloroglucinol derivatives with ATP citrate lyase inhibitory activities from Syzygium oblatum Wall.

Phytochemistry 2021 Apr 21;187:112765. Epub 2021 Apr 21.

School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address:

Nine undescribed acylphloroglucinol derivatives, oblatones A-I, along with three known ones, were isolated from Syzygium oblatum. Their structures were determined on the basis of extensive spectroscopic analysis, including NMR and MS data interpretation. Oblatones A and B possess an alkylated chromanone scaffold featuring a hemiketal moiety. Oblatones C and D are the first acylphloroglucinol derivatives with an α,β-unsaturated ketone lipid chain. Some of the isolates showed inhibitory effects on ATP citrate lyase in vitro. The binding mode of oblatone A was predicted by molecular docking.
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http://dx.doi.org/10.1016/j.phytochem.2021.112765DOI Listing
April 2021

Immediate versus delayed frozen embryo transfer in patients following a stimulated IVF cycle: a randomised controlled trial.

Hum Reprod 2021 Apr 22. Epub 2021 Apr 22.

Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.

Study Question: Is there any difference in the ongoing pregnancy rate after immediate versus delayed frozen embryo transfer (FET) following a stimulated IVF cycle?

Summary Answer: Immediate FET following a stimulated IVF cycle produced significantly higher ongoing pregnancy and live birth rate than did delayed FET.

What Is Known Already: Embryo cryopreservation is an increasingly important part of IVF, but there is still no good evidence to advise when to perform FET following a stimulated IVF cycle. All published studies are retrospective, and the findings are contradictory.

Study Design, Size, Duration: This was a randomised controlled non-inferiority trial of 724 infertile women carried out in two fertility centres in China between 9 August 2017 and 5 December 2018.

Participants/materials, Setting, Methods: Infertile women having their first FET cycle after a stimulated IVF cycle were randomly assigned to either (1) the immediate group in which FET was performed in the first menstrual cycle following the stimulated IVF cycle (n = 362) or (2) the delayed group in which FET was performed in the second or later menstrual cycle following the stimulated IVF cycle (n = 362). All FET cycles were performed in hormone replacement cycles. The randomisation sequence was generated using an online randomisation program with block sizes of four. The primary outcome was the ongoing pregnancy rate, defined as a viable pregnancy beyond 12 weeks of gestation. The non-inferiority margin was -10%. Analysis was performed by both per-protocol and intention-to-treat approaches.

Main Results And The Role Of Chance: Women in the immediate group were slightly younger than those in the delayed group (30.0 (27.7-33.5) versus 31.0 (28.5-34.2), respectively, P = 0.006), but the proportion of women ≤35 years was comparable between the two groups (308/362, 85.1% in the immediate group versus 303/362, 83.7% in the delayed group). The ongoing pregnancy rate was 49.6% (171/345) in the immediate group and 41.5% (142/342) in the delayed group (odds ratios 0.72, 95% CI 0.53-0.98, P = 0.034). The live birth rate was 47.2% (163/345) in the immediate group and 37.7% (129/342) in the delayed group (odds ratios 0.68, 95% CI 0.50-0.92, P = 0.012). The miscarriage rate was 13.2% (26 of 197 women) in the immediate group and 24.2% (43 of 178 women) in the delayed group (odds ratios 2.10; 95% CI 1.23-3.58, P = 0.006). The multivariable logistic regression, which adjusted for potential confounding factors including maternal age, number of oocytes retrieved, embryo stage at transfer, number of transferred embryos/blastocysts, reasons for FET, ovarian stimulation protocol and trigger type, demonstrated that the ongoing pregnancy rate was still higher in the immediate group.

Limitations, Reason For Caution: Despite randomisation, the two groups still differed slightly in the age of the women at IVF. The study was powered to consider the ongoing pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the observed differences between the treatment groups in terms of live birth rate should, therefore, be made with caution.

Wider Implications Of The Findings: Immediate FET following a stimulated IVF cycle had a significantly higher ongoing pregnancy and live birth rate than delayed FET. The findings of this study support immediate FET after a stimulated IVF cycle.

Study Funding/competing Interest(s): No external funding was used and no competing interests were declared.

Trial Registration Number: ClinicalTials.gov identifier: NCT03201783.

Trial Registration Date: 28 June 2017.

Date Of First Patient’s Enrolment: 9 August 2017.
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http://dx.doi.org/10.1093/humrep/deab071DOI Listing
April 2021

Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon.

Protein Cell 2021 Apr 19. Epub 2021 Apr 19.

State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China.

Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, non-human primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.
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http://dx.doi.org/10.1007/s13238-021-00835-wDOI Listing
April 2021

A Novel Chemiluminescence Probe for Sensitive Detection of Fibroblast Activation Protein-Alpha In Vitro and in Living Systems.

Anal Chem 2021 04 18;93(16):6501-6507. Epub 2021 Apr 18.

Shanghai Key Laboratory of Bioactive Small Molecules & Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, Shanghai 201203, P. R. China.

Fibroblast activation protein-alpha (FAPα) is a key modulator of the microenvironment in multiple pathologies and is becoming the next pan-cancer target for cancer diagnostics and therapeutics. Chemiluminescence (CL) luminophores are considered as one of the most sensitive families of probes for detection and imaging applications due to their high signal-to-noise ratio. Until now, however, no such effective CL probe was reported for FAPα detection. Herein, we developed a novel CL probe for the detection of endogenous FAPα activity by incorporating FAPα-specific dipeptide substrates (glycine-proline) to the improved Schaap's adamantylidene-dioxetane. In this manner, we designed three CL probes (, , and ) with the dipeptide substrate blocked by N-terminal benzyloxycarbonyl, --butoxycarbonyl or -quinoline-4-carboxylic acid, respectively, which was used as the masking group to restrain the chemiexcitation energy. Probe exhibited the optimal specificity for the discrimination of FAPα from dipeptidase IV and prolyl oligopeptidase, which was elucidated by molecular docking simulation. Upon FAPα cleavage, was turned on for the highly selective and sensitive detection of FAPα with a limit of detection of 0.785 ng/mL. Furthermore, the ability of to image FAPα was effectively demonstrated in vitro, including various biological samples (plasma and tissue preparations), and in living systems (tumor cells and tumor-bearing mice). Furthermore, this newly established probe could be easily extended to evaluate FAPα inhibitors. Overall, we anticipate that probe will offer a facile and cost-effective alternative in the early detection of pathologies, individual tailoring of drug therapy, and drug screening.
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http://dx.doi.org/10.1021/acs.analchem.1c00413DOI Listing
April 2021

Reconcile the debate over protective effects of BCG vaccine against COVID-19.

Sci Rep 2021 04 16;11(1):8356. Epub 2021 Apr 16.

Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Richards Building, D101, 3700 Hamilton Walk, Philadelphia, PA, 19104, USA.

While awaiting the COVID-19 vaccines, researchers have been actively exploring the effectiveness of existing vaccines against the new virus, among which the BCG vaccine (Bacillus Calmette-Guérin) receives the most attention. While many reports suggest a potential role for BCG immunization in ameliorating SARS-CoV-2 infection, these findings remain controversial. With country-level COVID-19 outbreak data from Johns Hopkins University Coronavirus Resource Center, and BCG program data from World Atlas of BCG Policies and Practices and WHO/UNICE, we estimated a dynamic model to investigate the effect of BCG vaccination across time during the pandemic. Our results reconcile these varying reports regarding protection by BCG against COVID-19 in a variety of clinical scenarios and model specifications. We observe a notable protective effect of the BCG vaccine during the early stage of the pandemic. However, we do not see any strong evidence for protection during the later stages. We also see that a higher proportion of vaccinated young population may confer some level of communal protection against the virus in the early pandemic period, even when the proportion of vaccination in the older population is low. Our results highlight that while BCG may offer some protection against COVID-19, we should be cautious in interpreting the estimated effectiveness as it may vary over time and depend on the age structure of the vaccinated population.
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http://dx.doi.org/10.1038/s41598-021-87731-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052320PMC
April 2021

High CFP score indicates poor prognosis and chemoradiotherapy response in LARC patients.

Cancer Cell Int 2021 Apr 13;21(1):205. Epub 2021 Apr 13.

Department of General Surgery, Peking University Third Hospital, Beijing, 100191, China.

Background: Preoperative tumor markers, inflammation, and nutritional status are considered important predictors of prognosis and tumor response in locally advanced rectal cancer (LARC) patients. This study aims to explore the prognostic and predictive role of carcinoembryonic antigen (CEA), the Fibrinogen-Albumin Ratio Index (FARI), the Prognostic Nutritional Index (PNI) in LARC patients and compared them with a novel combined CEA-FARI-PNI (CFP) scoring system.

Methods: A total of 138 LARC patients undergoing radical surgery following neoadjuvant chemoradiotherapy (NCRT) between January 2012 and March 2019 were enrolled. The X-tile program was used to determine the optimal cut-off values of CEA, FARI, and PNI, and CFP scoring system was constructed accordingly. The prognostic ability of these factors was assessed by the time-dependent receiver operating characteristic (ROC) curve, Kaplan-Meier, Cox regression, and logistic regression. Nomogram was established to evaluate the predictive role of these factors in tumor response.

Results: The optimal cut-off values of CEA, FARI, and PNI were 5.15 ng/l, 10.56%, and 42.25 g/L, respectively. The time-dependent ROC curve showed that compared to CEA, FARI, and PNI, CFP showed stable predictive efficacy for overall survival (OS) and disease-free survival (DFS). In multivariate analysis, CFP was the only factor that could independently predict OS (HR = 8.117, p = 0.001) and DFS (HR = 4.994, p < 0.001). Moreover, high CFP (OR = 3.693, p = 0.002) was also an independent risk factor of poor response. The area under the ROC curve (AUC) of the nomograms for predicting tumor response was better including CFP (0.717) than without CFP (0.656) (p < 0.05).

Conclusions: The CFP score was a more reliable marker for predicting OS, DFS, and NCRT efficacy in LARC patients, and the score could apparently improve predicted efficacy of the nomogram.
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http://dx.doi.org/10.1186/s12935-021-01903-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045186PMC
April 2021

Dexmedetomidine exhibits antiarrhythmic effects on human-induced pluripotent stem cell-derived cardiomyocytes through a Na/Ca channel-mediated mechanism.

Ann Transl Med 2021 Mar;9(5):399

Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center; School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Ventricular-like human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibit the electrophysiological characteristics of spontaneous beating. Previous studies demonstrated that dexmedetomidine (DMED), a highly selective and widely used α-adrenoceptor agonist for sedation, analgesia, and stress management, may induce antiarrhythmic effects, especially ventricular tachycardia. However, the underlying mechanisms of the DMED-mediated antiarrhythmic effects remain to be fully elucidated.

Methods: A conventional patch-clamp recording method was used to investigate the direct effects of DMED on spontaneous action potentials, pacemaker currents (), potassium (K) channel currents ( and ), sodium (Na) channel currents (), and calcium (Ca) channel currents () in ventricular-like hiPSC-CMs.

Results: DMED dose-dependently altered the frequency of ventricular-like spontaneous action potentials with a half-maximal inhibitory concentration (IC) of 27.9 µM (n=6) and significantly prolonged the action potential duration at 90% repolarization (APD). DMED also inhibited the amplitudes of the and without affecting the activation and inactivation curves of these channels. DMED decreased the time constant of the Na and Ca channel activation at potential -40 to -20 mv, and -20 mv. DMED increased the time constant of inactivation of the Na and Ca channels. However, DMED did not affect the , , , and their current-voltage relationship. The ability of DMED to decrease the spontaneous action potential frequency and the Na and Ca channel amplitudes, were not blocked by yohimbine, idazoxan, or phentolamine.

Conclusions: DMED could inhibit the frequency of spontaneous action potentials and decrease the and of hiPSC-CMs via mechanisms that were independent of the α-adrenoceptor, the imidazoline receptor, and the α-adrenoceptor. These inhibitory effects on hiPSC-CMs may contribute to the antiarrhythmic effects of DMED.
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http://dx.doi.org/10.21037/atm-20-5898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033317PMC
March 2021

A novel PPRC1 point mutation in a Chinese family with premature ovarian failure: A case study.

J Gene Med 2021 Apr 5:e3335. Epub 2021 Apr 5.

Obstertric and Gynecologic Hospital, Fudan University, Shanghai, China.

Background: Patients with premature ovarian failure (POF) have an at least 6-month history of amenorrhea and elevated follicle-stimulating hormone levels in plasma. Most of the POF causes are idiopathic and hereditary, and chromosomal abnormalities have been associated with POF development. A pedigree study was performed on a family with idiopathic POF to observe the possible link between gene mutation and POF development.

Methods: In total, eight women were diagnosed with POF and seven POF patients and five non-POF members from the same family were evaluated by whole exome sequencing and Sanger sequencing. An apoptotic assay, senescence staining, real-time polymerase chain reaction (qPCR) and overexpression of the peroxisome proliferator-activated receptor gamma coactivator-related 1 (PPRC1) gene were performed to examine the association of POF in vitro.

Results: Through whole exome sequencing and Sanger sequencing, a novel point mutation (NM_015062: c.2902C>T:p.Thr958Ile) was identified and verified in the PPRC1 gene on chromosome 10 (10q24.32). The point mutation only presented in all the seven POF cases and not in non-POF cases or public databases. Subsequent expression of PPRC1 in COV434 granulosa cells showed that PPRC1 might be involved in regulating granulosa cell apoptosis but not senescence-associated POF development.

Conclusions: A novel point mutation in the PPRC1 gene was identified by the pedigree study and by sequence analysis of the case series with idiopathic POF in the present study. The subsequent PPRC1 expression analysis showed that PPRC1 was not involved in senescence-associated POF development. Further studies will be needed to confirm the link between PPRC1 gene mutation and POF.
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http://dx.doi.org/10.1002/jgm.3335DOI Listing
April 2021

Cell-free decellularized cartilage extracellular matrix scaffolds combined with interleukin 4 promote osteochondral repair through immunomodulatory macrophages: In vitro and in vivo preclinical study.

Acta Biomater 2021 Mar 31. Epub 2021 Mar 31.

Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China. Electronic address:

Cartilage regeneration is a complex physiological process. Synovial macrophages play a critical immunomodulatory role in the acute inflammatory response surrounding joint injury. Due to the contrasting differences and heterogeneity of macrophage, the phenotype of macrophages are the key determinants of the healing response after cartilage injury. Biomaterials derived from extracellular matrix have been used for the repair and reconstruction of a variety of tissues by modulating the host macrophage response. However, the immunomodulatory effect of decellularized cartilage extracellular matrix (ECM) on macrophages has not been elucidated. It is necessary to clarify the immunomodulatory properties of decellularized cartilage matrix (DCM) to guide the design of cartilage regeneration materials. Here, we prepared porcine articular cartilage derived DCM and determined the response of mouse bone marrow-derived macrophages (BMDMs) to the pepsin-solubilized DCM (PDCM) in vitro. Macrophages activated by the PDCM could promote bone marrow-derived mesenchymal stem cells (BMSCs) invasion, migration, proliferation, and chondrogenic differentiation. Then, we verified that early optimization of the immunomodulatory effects of the cell-free DCM scaffold using IL-4 in vivo could achieve good cartilage regeneration in a rat knee osteochondral defect model. Therefore, this decellularized cartilage ECM scaffold combined with accurate and active immunomodulatory strategies provides a new approach for the development of cartilage regeneration materials. STATEMENT OF SIGNIFICANCE: This work reports a decellularized cartilage extracellular matrix (DCM) scaffold combined with an accurate and active immunomodulatory strategy to improve cartilage regeneration. Our findings demonstrated that the pepsin-solubilized DCM (PDCM) activated bone marrow-derived macrophages to polarize to a constructive macrophage phenotype. These polarized macrophages promoted bone marrow-derived mesenchymal stem cell invasion, migration, proliferation, and chondrogenic differentiation. DCM scaffolds combined with early-stage intra-articular injection of IL-4 created a wound-healing microenvironment and improved cartilage regeneration in a rat knee osteochondral defect model.
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http://dx.doi.org/10.1016/j.actbio.2021.03.054DOI Listing
March 2021

Bromodomain-containing proteins BRD1, BRD2, and BRD13 are core subunits of SWI/SNF complexes and vital for their genomic targeting in Arabidopsis.

Mol Plant 2021 Mar 24. Epub 2021 Mar 24.

State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address:

Switch defective/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes are multi-subunit machines that play vital roles in the regulation of chromatin structure and gene expression. However, the mechanisms by which SWI/SNF complexes recognize their target loci in plants are not fully understood. Here, we show that the Arabidopsis thaliana bromodomain-containing proteins BRD1, BRD2, and BRD13 are core subunits of SWI/SNF complexes and critical for SWI/SNF genomic targeting. These three BRDs interact directly with multiple SWI/SNF subunits, including the BRAHMA (BRM) catalytic subunit. Phenotypic and transcriptomic analyses of the brd1 brd2 brd13 triple mutant revealed that these BRDs act largely redundantly to control gene expression and developmental processes that are also regulated by BRM. Genome-wide occupancy profiling demonstrated that these three BRDs extensively colocalize with BRM on chromatin. Simultaneous loss of function of three BRD genes results in reduced BRM protein levels and decreased occupancy of BRM on chromatin across the genome. Furthermore, we demonstrated that the bromodomains of BRDs are essential for genomic targeting of the BRD subunits of SWI/SNF complexes to their target sites. Collectively, these results demonstrate that BRD1, BRD2, and BRD13 are core subunits of SWI/SNF complexes and reveal their biological roles in facilitating genomic targeting of BRM-containing SWI/SNF complexes in plants.
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http://dx.doi.org/10.1016/j.molp.2021.03.018DOI Listing
March 2021

Aspirin "Allergy"-Induced Thrombocytopenia: A Case Report.

J Asthma Allergy 2021 9;14:201-205. Epub 2021 Mar 9.

Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.

Aspirin is clinically widely used to inhibit platelet aggregation after coronary intervention. Herein we describe a case of aspirin-induced thrombocytopenia that may be related to allergy to aspirin. A 47-year-old man developed a delayed hypersensitivity reaction to aspirin, with pruritus, purpura and thrombocytopenia, increased peripheral blood eosinophils and enlarged inguinal lymph node. All the symptoms disappeared in 2 years after stopping aspirin. Aspirin-induced thrombocytopenia related to allergy is rarely reported. Aspirin hypersensitivity should be taken into consideration in case of unexplained thrombocytopenia in patients taking aspirin. Aspirin "allergy"-induced thrombocytopenia may involve both aspirin related IgG and IgE antibodies.
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http://dx.doi.org/10.2147/JAA.S292567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955731PMC
March 2021

Evaluation of CD49f as a novel surface marker to identify functional adipose-derived mesenchymal stem cell subset.

Cell Prolif 2021 May 11;54(5):e13017. Epub 2021 Mar 11.

School of Medicine, Nankai University, Tianjin, China.

Objectives: CD49f is expressed on a variety of stem cells and has certain effects on their cytological functions, such as proliferation and differentiation potential. However, whether CD49f is expressed on the surface of adipose tissue-derived mesenchymal stem cells (ADSCs) and its effect on ADSCs has not been clarified.

Materials And Methods: The effects of in vitro culture passage and inflammatory factor treatment on CD49f expression and the adhesion ability of ADSCs from mice and rats were investigated. CD49f cells were selected from rat ADSCs (rADSCs) by magnetic-activated cell sorting (MACS), and the cellular functions of CD49f ADSCs and unsorted ADSCs, including their clonogenic, proliferation, adipogenic and osteogenic differentiation, migration and anti-apoptotic capacities, were compared.

Results: CD49f expression and the adhesion ability of ADSCs decreased with increasing in vitro culture passage number. TNF-α and IFN-γ treatment decreased CD49f expression but increased the adhesion ability of ADSCs. After CD49f was blocked with an anti-CD49f antibody, the adhesion ability of ADSCs was decreased. No significant difference in clonogenic activity was observed between unsorted ADSCs and CD49f ADSCs. CD49f ADSCs had greater proliferation, adipogenic and osteogenic differentiation, migration and anti-apoptotic capacities than unsorted ADSCs.

Conclusion: In the current study, the expression of CD49f on ADSCs was identified for the first time. The expression of CD49f on ADSCs was influenced by in vitro culture passage number and inflammatory factor treatment. Compared with unsorted ADSCs, CD49f ADSCs exhibited superior cellular functions, thus may have great application value in mesenchymal stem cell (MSC)-based therapies.
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http://dx.doi.org/10.1111/cpr.13017DOI Listing
May 2021

Changes in plasma HDL and its subcomponents HDL2b and HDL3 regulate inflammatory response by modulating SOCS1 signaling to affect severity degree and prognosis of sepsis.

Infect Genet Evol 2021 Mar 5;91:104804. Epub 2021 Mar 5.

Department of Intensive Care Unit, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, China.

Objectives: To explore if SOCS1 is regulated by plasma HDL and its subcomponents HDL2b and HDL3 to affect inflammatory reaction then to influence the severity degree and prognosis of sepsis.

Methods: One hundred sepsis patients in ICU and 85 normal control persons from October 2018 to October 2019 in our hospital were enrolled. Adult male C57BL/6 mice were used to establish sepsis model by CLP method. HDL, CRP, and WBC count of human were measured using an auto-analyzer. Plasma HDL, IL-1β, and TNF-α proteins levels of mice were measured with ELISA. Microfluidic chip was used for plasma HDL2b and HDL3 detections. SOCS1 in liver and spleen of mice were measured by qRT-PCR. The relationship between plasma HDL//HDL2b and inflammatory indices/SOCS1 in liver/spleen was analyzed with spearman correlation coefficient method. The sepsis patients/mice were divided into non-survival and survival groups. The sepsis patients were divided into severe and mild sepsis patients based on the SOFA score or divided into high and low score groups according to the APACHE II score. The sepsis mice were divided into high and low score group based on the modified sepsis severity score criterion.

Results: Plasma HDL and HDL2b levels were significantly declined (P < 0.01), while HDL3 was normal in both sepsis patients and mice (P > 0.05). Plasma HDL and HDL2b were negatively associated with the serum CRP concentration and positively correlated with the prognosis and severity in sepsis patients (P < 0.05). Moreover, the downregulated plasma HDL but not HDL2b was negatively related to increased SOCS1 mRNA levels in liver and spleen of mice, which were positively connected with TNF-α and IL-1β protein levels (P < 0.05).

Conclusions: Plasma HDL is downregulated in sepsis, which may facilitate inflammatory reaction then activate the SOCS1 signaling to regulate the severity and affect prognosis of sepsis. The decline of plasma HDL2b content could aggravate the severity and poor prognosis of sepsis through facilitating inflammatory reaction. The plasma HDL3 is not involved in sepsis. The more and further explorations may be needed.
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http://dx.doi.org/10.1016/j.meegid.2021.104804DOI Listing
March 2021

Real-world virtual patient simulation to improve diagnostic performance through deliberate practice: a prospective quasi-experimental study.

Diagnosis (Berl) 2021 Mar 5. Epub 2021 Mar 5.

Center for Diagnostic Excellence, Armstrong Institute for Patient Safety and Quality, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objectives: Diagnostic errors are pervasive in medicine and most often caused by clinical reasoning failures. Clinical presentations characterized by nonspecific symptoms with broad differential diagnoses (e.g., dizziness) are especially prone to such errors.

Methods: We hypothesized that novice clinicians could achieve proficiency diagnosing dizziness by training with virtual patients (VPs). This was a prospective, quasi-experimental, pretest-posttest study (2019) at a single academic medical center. Internal medicine interns (intervention group) were compared to second/third year residents (control group). A case library of VPs with dizziness was developed from a clinical trial (AVERT-NCT02483429). The approach (VIPER - Virtual Interactive Practice to build Expertise using Real cases) consisted of brief lectures combined with 9 h of supervised deliberate practice. Residents were provided dizziness-related reading and teaching modules. Both groups completed pretests and posttests.

Results: For interns (n=22) vs. residents (n=18), pretest median diagnostic accuracy did not differ (33% [IQR 18-46] vs. 31% [IQR 13-50], p=0.61) between groups, while posttest accuracy did (50% [IQR 42-67] vs. 20% [IQR 17-33], p=0.001). Pretest median appropriate imaging did not differ (33% [IQR 17-38] vs. 31% [IQR 13-38], p=0.89) between groups, while posttest appropriateness did (65% [IQR 52-74] vs. 25% [IQR 17-36], p<0.001).

Conclusions: Just 9 h of deliberate practice increased diagnostic skills (both accuracy and testing appropriateness) of medicine interns evaluating real-world dizziness 'in silico' more than ∼1.7 years of residency training. Applying condensed educational experiences such as VIPER across a broad range of common presentations could significantly enhance diagnostic education and translate to improved patient care.
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http://dx.doi.org/10.1515/dx-2020-0127DOI Listing
March 2021

Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration.

Bioact Mater 2021 Sep 13;6(9):2711-2728. Epub 2021 Feb 13.

Department of Orthopedics, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Articular cartilage defect repair is a problem that has long plagued clinicians. Although mesenchymal stem cells (MSCs) have the potential to regenerate articular cartilage, they also have many limitations. Recent studies have found that MSC-derived exosomes (MSC-Exos) play an important role in tissue regeneration. The purpose of this study was to verify whether MSC-Exos can enhance the reparative effect of the acellular cartilage extracellular matrix (ACECM) scaffold and to explore the underlying mechanism. The results of in vitro experiments show that human umbilical cord Wharton's jelly MSC-Exos (hWJMSC-Exos) can promote the migration and proliferation of bone marrow-derived MSCs (BMSCs) and the proliferation of chondrocytes. We also found that hWJMSC-Exos can promote the polarization of macrophages toward the M2 phenotype. The results of a rabbit knee osteochondral defect repair model confirmed that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration. We demonstrated that hWJMSC-Exos can regulate the microenvironment of the articular cavity using a rat knee joint osteochondral defect model. This effect was mainly manifested in promoting the polarization of macrophages toward the M2 phenotype and inhibiting the inflammatory response, which may be a promoting factor for osteochondral regeneration. In addition, microRNA (miRNA) sequencing confirmed that hWJMSC-Exos contain many miRNAs that can promote the regeneration of hyaline cartilage. We further clarified the role of hWJMSC-Exos in osteochondral regeneration through target gene prediction and pathway enrichment analysis. In summary, this study confirms that hWJMSC-Exos can enhance the effect of the ACECM scaffold and promote osteochondral regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895679PMC
September 2021

Lnc-RNA LINC01279 induces endometriosis via targeting of HOXA10.

J Obstet Gynaecol Res 2021 May 3;47(5):1825-1836. Epub 2021 Mar 3.

Department of Reproductive Medicine and Genetics Center, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China.

Aim: To explore the regulatory role and molecular mechanism of lncRNA-LINC01279 in endometriosis (EMs).

Methods: Between September 2018 and July 2019, 20 EMs patients and 20 healthy subjects were recruited to detect the expression of lncRNA-LINC01279 in EMs and in normal endometrium via qRT-PCR. Autograft was used to establish EMs models on Spraque-Dawley (SD) rats, which was followed by taking volume measurements of EMs endometrium and observing pathological changes in the morphology of EMs via hematoxylin and eosin (H&E) staining. The qRT-PCR technique was further carried out to determine mRNA expression of lncRNA-LINC01279 and HOXA10 in the serum of EMs rats and LINC01279 shRNA-transfected rats, while the protein expression of HOXA10 was determined using a Western blot.

Results: EMs patients presented with upregulation of lncRNA-LINC01279 and downregulation of HOXA10 (p < 0.01 or 0.001). Online predictions further revealed that lncRNA-LINC01279 regulated the expression of HOXA10 via miRNA-135b. In EMs models, it was observed that there were a significantly enlarged endometrium and poor pathological morphology, significant upregulation of lncRNA-LINC01279, and downregulation of miR-135b and HOXA10 in serum (p < 0.05, 0.01 or 0.001). In the lncRNA-LINC01279 shRNA group, EMs rats, following treatment, had a sharp decrease in the volume of EMs endometrium, and an improvement in pathological morphology, while lncRNA-LINC01279 was downregulated, with upregulation of miR-135b and HOXA10 (p < 0.05, 0.01 or 0.001).

Conclusion: LncRNA-LINC01279, by the mechanism of targeting miR-135b, has the potential to downregulate the expression of HOXA10, and therefore, can promote the development and progression of EMs.
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http://dx.doi.org/10.1111/jog.14723DOI Listing
May 2021

Calculated indices of volatile organic compounds (VOCs) in exhalation for lung cancer screening and early detection.

Lung Cancer 2021 04 14;154:197-205. Epub 2021 Feb 14.

Department of Medicine Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Background: Breath analysis is a promising noninvasive technique that offers a wide range of opportunities to facilitate early diagnosis of lung cancer (LC).

Method: Exhaled breath samples of 352 subjects including 160 with lung cancer (LC), 70 with benign pulmonary nodule (BPN) and 122 healthy controls (HC) were analyzed through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS) to obtain the metabolic information from volatile organic compounds (VOCs). Statistical classification models were used to find diagnostic clusters of VOCs for the discrimination of HC, BPN and LC patients' early and advanced stages, as well as subtypes of LC. Receiver operator characteristics (ROC) curves with 5-fold validations were used to evaluate the accuracy of these models.

Results: The analysis revealed that 20, 19, 19, and 20 VOCs discriminated LC from HC, LC from BPN, histology and LC stages respectively. The calculated diagnostic indices showed a large area under the curve (AUC) to distinguish HC from LC (AUC: 0.987, 95 % confidence interval (CI): 0.976-0.997), BPN from LC (AUC: 0.809, 95 % CI: 0.758-0.860), NSCLC from SCLC (AUC: 0.939, 95 % CI: 0.875-0.995) and Stage III from stage III-IV (AUC: 0.827, 95 % CI: 0.768-0.886). The comparison between the high-risk groups (BPN and HC smokers) and early stages LC resulted in the AUC of 0.756 (95 %CI: 0.681-0.817) for BPN vs. early stage LC and AUC of 0.986 (95 % CI: 0.972-0.994) for HC smoker vs. early stage LC.

Conclusion: Volatome of breath of the LC patients was significantly different from that of both BPN patients and HC and showed an ability of distinguishing early from advance stage LC and NSCLC from SCLC. We conclude that the volatome has a potential to help improve early diagnosis of LC.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.006DOI Listing
April 2021

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging.

ACS Chem Neurosci 2021 03 2;12(6):1018-1030. Epub 2021 Mar 2.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.

κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent κOR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure-activity relationships (SARs) of arylacetamides in conferring κOR agonistic activities could be reproduced by these analogues. Thus, a series of -cyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound with a 3',4'-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the κOR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound displayed moderately selective κOR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors . The resultant SARs were inconsistent with that of classical arylacetamides as κOR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring κOR activities.
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http://dx.doi.org/10.1021/acschemneuro.1c00034DOI Listing
March 2021

When Does Teacher Support Reduce Depression in Students? The Moderating Role of Students' Status as Left-Behind Children.

Front Psychol 2021 12;12:608359. Epub 2021 Feb 12.

Faculty of Artificial Intelligence in Education, Central China Normal University, Wuhan, China.

Teacher support (TS) makes students feel loved and cared for because they believe that their teachers will provide them with opportunities to make choices, support them in independent problem solving, and understand their inner feelings. High TS levels reduce depression and anxiety, thereby improving students' mental well-being. This cross-sectional study involved 3,573 students from 29 schools in 16 counties/cities of six provinces, namely, Guizhou, Hubei, Jiangxi, Shanxi, Sichuan, and Yunnan. The aim was to examine the impact of TS on students' level of depression. The results indicated that for children in elementary schools, their status as left-behind children (LBC) played a moderating role between TS and depression. The level of depression in non-LBC children decreased significantly with increases in TS, but the reduction for LBC children was not significant. For children in middle/junior high schools, their LBC status did not play a moderating role between TS and depression. TS was negatively correlated with the children's level of depression, but there was a significant positive relationship between their LBC status and depression. The theoretical and practical significance of the research findings were further discussed.
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http://dx.doi.org/10.3389/fpsyg.2021.608359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907653PMC
February 2021

On non-autonomous differential-difference AKP, BKP and CKP equations.

Proc Math Phys Eng Sci 2021 Jan 20;477(2245):20200717. Epub 2021 Jan 20.

School of Mathematics, University of Leeds, Leeds LS2 9JT, UK.

Based on the direct linearization framework of the discrete Kadomtsev-Petviashvili-type equations presented in the work of Fu & Nijhoff (Fu W, Nijhoff FW. 2017 Direct linearizing transform for three-dimensional discrete integrable systems: the lattice AKP, BKP and CKP equations. , 20160915 (doi:10.1098/rspa.2016.0915)), six novel non-autonomous differential-difference equations are established, including three in the AKP class, two in the BKP class and one in the CKP class. In particular, one in the BKP class and the one in the CKP class are both in (2 + 2)-dimensional form. All the six models are integrable in the sense of having the same linear integral equation representations as those of their associated discrete Kadomtsev-Petviashvili-type equations, which guarantees the existence of soliton-type solutions and the multi-dimensional consistency of these new equations from the viewpoint of the direct linearization.
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http://dx.doi.org/10.1098/rspa.2020.0717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897632PMC
January 2021

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial.

Prostate 2021 May 26;81(6):326-338. Epub 2021 Feb 26.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival.

Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS).

Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels.

Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.
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http://dx.doi.org/10.1002/pros.24110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018565PMC
May 2021

Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration.

Stem Cells Int 2021 12;2021:8882505. Epub 2021 Feb 12.

Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing 100853, China.

Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.
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http://dx.doi.org/10.1155/2021/8882505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895563PMC
February 2021

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

J Clin Oncol 2021 Apr 22;39(12):1371-1382. Epub 2021 Feb 22.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).

Methods: The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).

Results: The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.

Conclusion: This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.
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http://dx.doi.org/10.1200/JCO.20.02759DOI Listing
April 2021

Chemically Modified SDF-1α mRNA Promotes Random Flap Survival by Activating the SDF-1α/CXCR4 Axis in Rats.

Front Cell Dev Biol 2021 4;9:623959. Epub 2021 Feb 4.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.
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http://dx.doi.org/10.3389/fcell.2021.623959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890013PMC
February 2021

Taurine improves the differentiation of neural stem cells in fetal rats with intrauterine growth restriction via activation of the PKA-CREB-BDNF signaling pathway.

Metab Brain Dis 2021 Jun 20;36(5):969-981. Epub 2021 Feb 20.

Department of Neonatology and NICU, Beijing Chaoyang District Maternal and Child Healthcare Hospital, Beijing, 100021, China.

Intrauterine growth restriction (IUGR) affects brain neural stem cell (NSC) differentiation. In the present study, we investigated whether taurine supplementation may improve NSC differentiation in IUGR fetal rats via the protein kinase A-cyclic adenosine monophosphate (cAMP) response element protein-brain derived neurotrophic factor (PKA-CREB-BDNF) signaling pathway. The IUGR fetal rat model was established with a low-protein diet. Fresh subventricular zone (SVZ) tissue from the fetuses on the 14th day of pregnancy was microdissected and dissociated into single-cell suspensions, then was cultured to form neurospheres. The neurospheres were divided into the control group, the IUGR group, the IUGR+taurine (taurine) group, the IUGR+H89 (H89) group and the IUGR+taurine+H89 (taurine+H89) group. The mRNA and protein expression levels of PKA, CREB and BDNF were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting (WB). Tuj-1-positive neurons and GFAP-positive glial cells were detected by immunofluorescence. The total number of proliferating NSCs and the percentage of Tuj-1-positive neurons in the IUGR group were lower than those in the control group, but the percentage of GFAP-positive cells was higher in the IUGR group than in the control group. Taurine supplementation increased the total number of neural cells and the percentage of Tuj-1-positive neurons, and reduced the percentage of GFAP-positive cells among differentiated NSCs after IUGR. H89 reduced the total number and percentage of Tuj-1-positive neurons and increased the percentage of GFAP-positive cells. The mRNA and protein levels of PKA, CREB, and BDNF were lower in the IUGR group. The mRNA and protein expression levels of these factors were increased by taurine supplementation but reduced by the addition of H89. Taurine supplementation increased the ratio of neurons to glial cells and prevented gliosis in the differentiation of NSCs in IUGR fetal rats by activating the PKA-CREB-BDNF signaling pathway.
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http://dx.doi.org/10.1007/s11011-021-00672-0DOI Listing
June 2021

Prospective, Single-Arm Trial Evaluating Changes in Uptake Patterns on Prostate-Specific Membrane Antigen (PSMA)-Targeted F-DCFPyL PET/CT in Patients with Castration-Resistant Prostate Cancer Starting Abiraterone or Enzalutamide.

J Nucl Med 2021 Feb 19. Epub 2021 Feb 19.

Johns Hopkins University School of Medicine, United States.

Positron emission tomography (PET) with small molecules targeting prostate-specific membrane antigen (PSMA) is being adopted as a clinical standard for prostate cancer (PCa) imaging. In this study, we evaluated changes in uptake on PSMA-targeted PET in men starting abiraterone or enzalutamide. This prospective, single-arm, two-center, exploratory clinical trial enrolled men with metastatic castration-resistant prostate cancer (CRPC) initiating abiraterone or enzalutamide. Each patient was imaged with F-DCFPyL at baseline and within 2-4 months after starting therapy. Patients were followed for up to 48 months from enrollment. A central review evaluated baseline and follow-up PET scans recording change in maximum standardized uptake value (SUV) at all disease sites and classifying the pattern of change. Two parameters: the delta percent SUV (DPSM) of all lesions and the delta absolute SUV (DASM) of all lesions were derived. Kaplan-Meier curves were used to estimate time to therapy change (TTTC) and overall survival (OS). Sixteen evaluable patients were accrued to the study. Median TTTC was 9.6 months (95% confidence interval (CI), 6.9-14.2) and median OS was 28.6 months (95% CI 18.3-not available (N/A)). Patients with a mixed-but-predominantly-increased pattern of radiotracer uptake had shorter TTTC and OS. Men with low DPSM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS 37.2 months (95% CI 28.9-N/A), while those with high DPSM had median TTTC 6.5 months (95% CI 4.6-N/A, = 0.0001) and median OS 17.8 months (95% CI 13.9-N/A, = 0.02). Men with low DASM had median TTTC 12.2 months (95% CI 11.3-N/A) and median OS N/A (95% CI 37.2 months-N/A), while those with high DASM had median TTTC 6.9 months (95% CI 6.1-N/A, = 0.003) and median OS 17.8 months (95% CI 13.9-N/A, = 0.002). Findings on PSMA-targeted PET 2-4 months after initiation of abiraterone or enzalutamide are associated with TTTC and OS. Development of new lesions and/or increasing intensity of radiotracer uptake at sites of baseline disease are poor prognostic findings suggesting shorter TTTC and OS.
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http://dx.doi.org/10.2967/jnumed.120.259069DOI Listing
February 2021

Meta-analysis of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in Henoch-Schonlein purpura and its complications.

Int Immunopharmacol 2021 May 12;94:107454. Epub 2021 Feb 12.

Sichuan Provincial Center for Gynecology and Breast Diseases, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China. Electronic address:

Objective: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with the severity of Henoch-Schonlein purpura (HSP). Therefore, we conducted a meta-analysis to evaluate the clinical significance of NLR and PLR in HSP and its complications.

Methods: A comprehensive literature search was conducted by searching the PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang, VIP, and SinoMed databases from their inception to September 31, 2020. We used the standard mean difference (SMD) with a 95% confidence interval (CI) to estimate the pooled effect and used subgroup analysis to investigate heterogeneity.

Results: A total of 1,691 HSP patients and 563 healthy controls (HCs) from 15 studies were included in the analysis. The NLR value was significantly higher in 431 HSP patients with gastrointestinal complications (HSP-GCs) than that in 833 HSP patients without GCs (SMD = 1.09, 95% CI: 0.62-1.57, P < 0.001); in 83 HSP adult patients with renal involvement (HSP-RI) than that in 131 adult HSP patients without RI (SMD = 0.33, 95% CI: 0.05-0.60, P = 0.021); and in 831 HSP patients than that in 563 HCs (SMD = 0.70, 95% CI: 0.51-0.89, P < 0.001). The PLR was significantly higher in 417 HSP patients than that in 264 HCs (SMD = 0.39, 95% CI: 0.06-0.71, P = 0.02).

Conclusions: NLR could serve as a useful biomarker to predict GCs and RI in patients with HSP. However, further well-designed and large cohort studies are warranted to confirm these findings.
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http://dx.doi.org/10.1016/j.intimp.2021.107454DOI Listing
May 2021

Longitudinal Trends of Financial Toxicity in Patients With Lung Cancer: A Prospective Cohort Study.

JCO Oncol Pract 2021 Feb 8:OP2000721. Epub 2021 Feb 8.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Cancer therapy is associated with severe financial burden. However, the magnitude and longitudinal patient relationship with financial toxicity (FT) in the initial course of therapy is unclear.

Methods: Patients with stage II-IV lung cancer were recruited in a prospective longitudinal study between July 2018 and March 2020. FT was measured via the validated COmprehensive Score for financial Toxicity (COST) at the time of cancer diagnosis and at 6-month follow-up (6MFU). 6MFU data were compared with corresponding baseline data. A lower COST score indicates increased financial hardship.

Results: At the time of analysis, 215 agreed to participate. Subsequently, 112 patients completed 6MFU. On average, slightly more FT was observed at diagnosis compared with 6MFU (median COST 25 COST 27; < .001); however, individual patients experienced large changes in FT. At 6MFU, 27.7% of patients had made financial sacrifices to pay for treatment but only 4.5% refused medical care based on cost. Median reported out-of-pocket (OOP) costs for the initial 6 months of cancer treatment was $2,496 (range, $0-25,900). Risk factors for FT at diagnosis were unique from risk factors at 6MFU. Actual OOP expenses were not correlated with FT; however, inability to predict upcoming treatment expenses resulted in higher FT at 6MFU.

Discussion: FT is a pervasive challenge during the initiation of lung cancer treatment. Few patients are willing to sacrifice medical care regardless of the cost. Risk factors for FT evolve, resulting in unique interventional targets throughout therapy.
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http://dx.doi.org/10.1200/OP.20.00721DOI Listing
February 2021