Publications by authors named "Jun Ren"

1,132 Publications

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Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT receptors.

J Mol Cell Cardiol 2021 Sep 20. Epub 2021 Sep 20.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai 200032, China. Electronic address:

It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.
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http://dx.doi.org/10.1016/j.yjmcc.2021.09.006DOI Listing
September 2021

The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes.

Physiol Rep 2021 Sep;9(17):e15011

Department of Biology, Western Wyoming College, Rock Springs, Wyoming, USA.

RNA binding motif 20 (RBM20) cardiomyopathy has been detected in approximately 3% of populations afflicted with dilated cardiomyopathy (DCM). It is well conceived that RBM20 cardiomyopathy is provoked by titin isoform switching in combination with resting Ca leaking. In this study, we characterized the cardiac function in Rbm20 knockout (KO) rats at 3-, 6-, 9-, and 12-months of age and examined the effect of the ryanodine receptor stabilizer S107 on resting intracellular levels and cardiomyocyte contractile properties. Our results revealed that even though Rbm20 depletion promoted expression of larger titin isoform and reduced myocardial stiffness in young rats (3 months of age), the established DCM phenotype required more time to embellish. S107 restored elevated intracellular Ca to normal levels and ameliorated cardiomyocyte contractile properties in isolated cardiomyocytes from 6-month-old Rbm20 KO rats. However, S107 failed to preserve cardiac homeostasis in Rbm20 KO rats at 12 months of age, unexpectedly, likely due to the existence of multiple pathogenic mechanisms. Taken together, our data suggest the therapeutic promises of S107 in the management of RBM20 cardiomyopathy.
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http://dx.doi.org/10.14814/phy2.15011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440945PMC
September 2021

Necrolytic migratory erythema-like eruption and paradoxical psoriasis associated with adalimumab treatment.

J Dermatol 2021 Sep 6. Epub 2021 Sep 6.

Department of Dermatology, Zhongshan Hospital Xiamen University, Xiamen, China.

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http://dx.doi.org/10.1111/1346-8138.16140DOI Listing
September 2021

Nanobody-loaded immunosorbent for highly-specific removal of interleukin-17A from blood.

J Chromatogr A 2021 Sep 18;1654:462478. Epub 2021 Aug 18.

Liaoning Key Laboratory of Molecular Recognition and imaging, School of Bioengineering, Dalian University of Technology, No.2 Linggong Road, Dalian, Liaoning 116023, PR China. Electronic address:

Elimination of overproduced cytokines from blood can relieve immune system disorders caused by hypercytokinemia. Due to the central roles of interleukin-17A (IL-17A) plays in regulating the immunity and inflammatory responses in humans, here, a novel immunosorbent containing anti-IL-17A nanobodies (Nbs) was constructed for IL-17A removal from blood. The theoretical maximum adsorption capacity estimated from the Langmuir isotherm is up to 11.55 mg/g gel, which is almost consistent with the saturated adsorption capacity determined in dynamic adsorption. The in vitro plasma perfusion test demonstrated a remarkable adsorptive performance of the Nb-coupled sorbent since more than 75% IL-17A could be eliminated under the plasma/sorbent ratio of 1000:1. These results indicated the Nb-loaded immunosorbent can provide a simple and economic platform technology for immunoaffinity depletion of single or even multiple cytokines from plasma.
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http://dx.doi.org/10.1016/j.chroma.2021.462478DOI Listing
September 2021

Intrauterine hyperglycemia impairs memory across two generations.

Transl Psychiatry 2021 Aug 20;11(1):434. Epub 2021 Aug 20.

Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.

Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.
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http://dx.doi.org/10.1038/s41398-021-01565-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379206PMC
August 2021

Effects of dominant plant growth on the nutrient composition and bacterial community structure of manganese residues.

Int J Phytoremediation 2021 Aug 12:1-11. Epub 2021 Aug 12.

School of Geography and Resources, Guizhou Education University, Guiyang, China.

The rhizospheres of three dominant plant species (, and ) growing in manganese residue disposal sites in eastern Guizhou Province, China, were analyzed to study the effects of plant growth on the nutrient levels and bacterial community structure of two types of manganese residues. The results showed that the growth of the three species improved the nutritional composition of manganese residues; the available nitrogen (AN) contents of the manganese mine residue significantly increased by 29.56-60.78% while the available phosphorus (AP) contents of the electrolytic manganese residue significantly increased by 30.24-44.41% compared to those in unvegetated manganese residue. The diversity of the bacterial community in the manganese mine residue increased significantly due to plant growth. , , and were the dominant phyla in both manganese residues. and GP6 were the dominant bacterial genera. The relative abundance of the phylum was significantly higher in the manganese mine residue than in the control and that of the genus was lower, which indicated improvements in the microenvironment. Correlation analysis showed that OM and AN were the main nutrient factors affecting the bacterial community structure in the manganese mine residue. At present, research on the phytoremediation of manganese residue disposal sites focuses mostly on the investigation of different plant types and their heavy metal accumulation and transformation characteristics. However, comparative studies of the differences in growth matrix characteristics between plant growth areas and exposed areas are lacking. In addition, dominant plant species are regionally distributed. The previous studies were mostly concentrated in Chongqing, Guangxi, and Hunan in China. The eastern region of Guizhou Province is located in the "Manganese Triangle" area of China, where the manganese resources account for about 50% of the national total. There is no report on the phytoremediation of manganese residue disposal sites in this region. Therefore, the rhizospheres of three dominant plant species (, , and ) growing in manganese residue disposal sites in eastern Guizhou Province, China, were analyzed to study the effects of plant growth on the nutrient levels and bacterial community structure of two types of manganese residues (manganese mine residue and electrolytic manganese residue). This study could provide useful theoretical information to benefit the ecological restoration of manganese residue disposal sites.
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http://dx.doi.org/10.1080/15226514.2021.1957769DOI Listing
August 2021

NDP52 Protects against Myocardial Infarction-Provoked Cardiac Anomalies through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.

Antioxid Redox Signal 2021 Aug 12. Epub 2021 Aug 12.

Zhongshan Hospital Fudan University, 92323, Cardiology, Shanghai, Shanghai, China.

Aims: Acute myocardial infarction (MI), caused by acute coronary artery obstruction, is a common cardiovascular event leading to mortality. Nuclear dot protein 52 (NDP52) is an essential selective autophagy adaptor, although its function in MI is still obscure. This study was designed to examine the function of NDP52 in MI and the associated mechanisms.

Results: Our results revealed that MI challenge overtly impaired myocardial geometry and systolic function, along with cardiomyocyte apoptosis, myocardial interstitial fibrosis, and mitochondrial damage, and NDP52 nullified such devastating responses. Further studies showed the blockade of mitochondrial clearance is related to MI-induced buildup of damaged mitochondria. Mechanistic approaches depicted that 7-day MI induced abnormal mitophagy flux, resulting in poor lysosomal clearance of injured mitochondria. NDP52 promoted mitophagy flux through recruitment of RAB7 and TBK1. Upon protein colocalization, TBK1 phosphorylated RAB7, in line with the finding that chloroquine or a TBK1 inhibitor reversed NDP52-dependent beneficial responses.

Innovation: This study denoted a novel mechanism that NDP52 promotes cardioprotection against ischemic heart diseases through interaction with TBK1 and RAB7, leading to RAB7 phosphorylation, induction of mitophagy to clear ischemia-induced impaired mitochondria, thus preventing cardiomyocyte apoptosis in MI.

Conclusion: Our results indicate that NDP52 promotes autophagic flux and clears damaged mitochondria to diminish ROS and cell death in a TBK1/RAB7-dependent manner and thus limits MI induced injury.
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http://dx.doi.org/10.1089/ars.2020.8253DOI Listing
August 2021

Effect of phosphogypsum on the properties of magnesium phosphate cement paste with low magnesium-to-phosphate ratio.

Sci Total Environ 2021 Jul 28;798:149262. Epub 2021 Jul 28.

School of Architecture and Planning, Yunnan University, Kunming 650051, China. Electronic address:

The incorporation of phosphogypsum (PG) in magnesium potassium phosphate cement (MPPC) can promote the utilization of PG not only by utilising the phosphate impurity in PG, but also by immobilising the heavy metals with MPPC. This paper investigates the feasibility of the incorporation of PG in preparing MPPC. Both early age properties, including workability and setting time, and hardened properties of compressive strength and microstructure, of PG-incorporated MPPC paste were investigated, and the hydration mechanism was explored. The results indicated that the addition of PG increased the workability of MPPC and extended the setting time of MPPC. However, incorporation of 20% PG slightly reduced the compressive strength because higher PG content led to the loose microstructure. Moreover, the addition of PG did not change the formation of hydration product, while it only reduced the hydration heat. Finally, compared to PG, the concentration of leached heavy metals of MPPC with PG was significantly reduced after 28 days curing.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149262DOI Listing
July 2021

FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis.

Metabolism 2021 Sep 29;122:154840. Epub 2021 Jul 29.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Objective: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies.

Methods And Materials: WT and FUNDC1 mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.).

Results: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obese rat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis.

Conclusions: These data suggest that FUNDC1 deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis.
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http://dx.doi.org/10.1016/j.metabol.2021.154840DOI Listing
September 2021

NLR value and IL-18 level and their clinical significance in patients with deep vein thrombosis after receiving the surgery for spinal degeneration.

Am J Transl Res 2021 15;13(6):7156-7163. Epub 2021 Jun 15.

Department of Spine Surgery, The Sixth Affiliated Hospital of Xinjiang Medical University Urumqi, Xinjiang Uygur Autonomous Region, China.

Objective: To investigate the value of the neutrophil-to-lymphocyte ratio (NLR) and Interleukin 18 (IL-18) level in patients with deep vein thrombosis after receiving surgery for spinal degeneration; and we explore their significance in clinical practice.

Methods: This study was conducted in 296 patients who were treated in our hospital for spinal degeneration. After surgery, these patients were followed up for 1 month. After performing the color Doppler ultrasound examination, patients were divided into the thrombus group (n = 72) and the non-thrombus group (n = 224) based on the occurrence of deep vein thrombosis. Baseline data, NLR values and IL-18 levels before surgery, and at 1, 3, 5, and 7 days after surgery were compared between the two groups. Logistic regression analysis was implemented to analyze the risk factors for postoperative deep vein thrombosis. Patients in the thrombosis group were allocated to the mild, moderate, and severe group on the basis of the degree of thrombosis. NLR values and IL-18 levels at 3 days after surgery were compared among the three groups. The correlations between both NLR value and IL-18 level and the severity of deep vein thrombosis were analyzed with Pearson correlation. Receiver operating characteristic curve was used to assess the clinical value of NLR value and IL-18 level at 3 days after surgery in predicting postoperative deep vein thrombosis.

Results: There were significant differences concerning age, the history of diabetes, and obesity between the two groups (all P<0.05). NLR values and IL-18 levels in both groups after surgery were increased when compared with before surgery (all P<0.01). In addition, NLR values and IL-18 levels reached a peak at 3 days after surgery. Compared with the non-thrombus group, NLR values and IL-18 levels in the thrombus group at 1, 3, 5, and 7 days after surgery were increased (all P<0.01). NLR value and IL-18 level in the thrombosis group at 3 days after surgery were increased with a worsened degree of thrombosis. In other words, both NLR value and IL-18 level were positively correlated with the degree of deep vein thrombosis. The results of logistic regression analysis displayed that age ≥60 years old, body mass index ≥23 kg/m, NLR value >4.34%, and IL-18 level >115.71 ng/mL were independent risk factors for postoperative deep vein thrombosis. The results of the ROC curve showed that the area under curves, which represent the formation of postoperative deep vein thrombosis, were above 0.7 when using NLR value and IL-18 level at 3 days after surgery (both P<0.001).

Conclusion: Compared with the non-thrombus group, NLR value and IL-18 level in the thrombosis group after receiving surgery for spinal degeneration are significantly increased. In addition, the more severe the thrombosis is, the higher the NLR value and IL-18 level at 3 days after surgery. Therefore, NLR value and IL-18 level at 3 days after surgery have certain clinical value in predicting postoperative deep vein thrombosis and prognosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290746PMC
June 2021

Persistent fifth aortic arch: a single-center experience, case series.

Transl Pediatr 2021 Jun;10(6):1566-1572

Division of Cardiology, the Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.

Background: Persistent fifth aortic arch (PFAA) is an extremely rare congenital cardiovascular malformation and there is limited data in the literature. The objective of this study is to enhance our understanding and diagnosis of PFAA from echocardiography and computed tomography angiography (CTA) findings, and to evaluate the application of echocardiography in the diagnosis of PFAA.

Methods: We retrospectively reviewed five cases of PFAA diagnosed from October 2016 to September 2019 at the Affiliated Children's Hospital of Capital Institute of Pediatrics. We described their diagnosis by echocardiography and CTA findings, and medical history.

Results: Five cases of PFAA were identified in the study. Patients aged from 3 to 48 months and weighed from 4 to 12 kg presented different clinical symptoms upon clinical examination. All the patients completed a primary echocardiographic assessment; however, the first two patients were misdiagnosed by echocardiography and was confirmed by supplemental CTA while the other three patients were directly diagnosed by echocardiography. Surgery was necessary for three patients, two of whom accepted and one refused. The other two patients only needed a follow-up assessment, which showed good results.

Conclusions: The clinical manifestation of PFAA in our patient population was atypical, and their diagnosis depended on the use of echocardiography. In the case of uncertainty, the final diagnosis was confirmed by CTA. Although the nomenclature and embryonic origin of PFAA remains controversial, the accurate diagnosis of aortic arch abnormalities and associated malformations are imperative for time-sensitive treatments.
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http://dx.doi.org/10.21037/tp-20-433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261588PMC
June 2021

Benzotriazole-5-carboxylic as a mixed-mode ligand for chromatographic separation of antibody with enhanced adsorption capacity.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Aug 11;1179:122652. Epub 2021 Mar 11.

Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian 116023, PR China. Electronic address:

Mixed-mode chromatography provides a promising strategy for industrial protein purification for its potential merit of balancing efficiency and cost-effectiveness. However, mixed-mode media with satisfactory selectivity and binding capacity towards antibody are still urgently needed. A new type of mixed-mode chromatography resin was prepared using benzotriazole-5-carboxylicas as ligand (BTA MM), and its application in antibody separation was explored. A typical pH-dependent protein binding was observed, and the neutral condition was favorable for antibody adsorption. Dynamic binding capacity of human immunoglobulin G (hIgG) was 57.7 mg/mL at pH 7.4 (10 mM phosphate buffer, containing 150 mM NaCl), while elution with acidic solutions (pH 3-4) could achieve a recovery of more than 85%. Protein adsorption on the resin showed a salt-independent manner, thus it could work under physiological solution conditions, with satisfied antibody selectivity. One-step purification of antibody components from human serum samples could obtain a product with the purity more than 84%. Satisfied performance was also observed when the adsorbent was used for purifying a IgG1-type monoclonal antibody (mAb) from cell culture supernatant. In addition, the benzotriazole adsorbent has been found stable enough to withstand autoclave sterilization and other harsh conditions, including 1 M NaOH, 1 M HCl, and 75% ethanol. The results proved the potential of this type of mixed-mode chromatography medium for industrial antibody purification.
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http://dx.doi.org/10.1016/j.jchromb.2021.122652DOI Listing
August 2021

Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models.

Sci Transl Med 2021 07;13(602)

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.
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http://dx.doi.org/10.1126/scitranslmed.abd4816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409338PMC
July 2021

High-Throughput Screening of Element-Doped Carbon Nanotubes Toward an Optimal One-Dimensional Superconductor.

J Phys Chem Lett 2021 Jul 13;12(28):6667-6675. Epub 2021 Jul 13.

Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.

In order to search for optimal one-dimensional (1D) superconductors with a high transition temperature (), we performed high-throughput computation on the phonon dispersion, electron-phonon coupling (EPC), and superconducting properties of (5,0), (3,3), and element-doped (3,3) carbon nanotubes (CNTs) based on first-principles calculations. We find that the CNT (5,0) is superconductive with of 7.9 K, while the (3,3) CNT has no superconductivity. However, by high-throughput screening of about 50 elements in the periodic table, we identified that 14 elemental dopants can make the (3,3) CNT dynamically stable and superconducting. The high ≈ 28 K suggests that the Si-doped (3,3) CNT is an excellent one-dimensional (1D) superconductor. In addition, the Al-, In-, and La-doped (3,3) CNTs are also great 1D superconductor candidates with a of about 18, 17, and 29 K, respectively. These results may inspire the synthesis and discovery of optimal high- 1D superconductors experimentally.
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http://dx.doi.org/10.1021/acs.jpclett.1c02000DOI Listing
July 2021

Aging as a risk factor for cardiac surgery: Blunted ischemic-reperfusion stress response?

Authors:
Lin Wang Jun Ren

J Card Surg 2021 Oct 11;36(10):3641-3642. Epub 2021 Jul 11.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.

Biological aging is commonly associated with compromised cardiovascular function. In particular, cardiac aging is featured by unfavorable left ventricular remodeling, loss of compliance, and poor contractile reserve. Among possible contributing factors for cardiovascular aging, dampened autophagy response has received much attention. Recent evidence also noted a decline in ischemia-reperfusion (I/R) response and mitochondrial content in aging. I/R stress is commonly seen in the setting of cardiac surgery representing a clinical dilemma accompanied by possible myocardial injury if not handled correctly. Although overproduction of reactive oxygen species has been indicated to play a role in aging-associated more pronounced I/R injury, little is known for the mechanism of action (in particular the role of autophagy and mitophagy) and possible sequelae of poor I/R stress response in aging.
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http://dx.doi.org/10.1111/jocs.15806DOI Listing
October 2021

Prognostic Value of Coronary Artery Calcification Identified by the Semi-quantitative Weston Method in the Emergency Room or Other Hospitalized Patients.

Front Cardiovasc Med 2021 16;8:684292. Epub 2021 Jun 16.

Heart and Vascular Institute, Stamford Hospital, Stamford, CT, United States.

Coronary artery calcification (CAC) may provide insight to the patients' coronary artery disease (CAD) risks and influence early intervention. With increasing use of non-gated CT scans in clinical practice, the visual coronary artery scoring system (Weston Method) could quickly provide clinicians with important information of CAC for patient triage and management. We retrospectively studied the available CT imaging data and estimated CAC burden using the Weston method in 493 emergency room or other hospitalized patients. The Weston scores were calculated by the sum of the score for each vessel including the left main, left anterior descending, left circumflex artery and right coronary artery (range 0-12). The primary endpoint was a composite of the major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, stroke, and coronary revascularization. During a median follow-up of 85 months, a total of 25 (5.1%) MACE were recorded and 57 (11.2%) patients died from any causes. Detectable CAC was most common (96%) in the left anterior descending coronary arteries. Multivariable analysis showed that CAC total scores were independent predictors for MACE and all-cause mortality. Receiver operating characteristic analysis showed that CAC total score ≥5 was the optimal cutoff value for predicting MACEs. In the emergency room and hospitalized patients, the semi-quantitation of CAC burden using the Weston score system was related to the long-term cardiovascular outcomes including mortality. Clinicians and radiologists should maximize the value of non-contrast chest CT images by reporting CAC details.
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http://dx.doi.org/10.3389/fcvm.2021.684292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248783PMC
June 2021

Dynamic Modeling and Frequency Characteristic Analysis of a Novel 3-PSS Flexible Parallel Micro-Manipulator.

Authors:
Jun Ren Qiuyu Cao

Micromachines (Basel) 2021 Jun 10;12(6). Epub 2021 Jun 10.

School of Mechanical Engineering, Hubei University of Technology, Wuhan 430068, China.

Dynamic modeling and frequency characteristic analysis of a novel 3-PSS (three-prismatic-spherical-spherical) flexible parallel micro-manipulator with three translational DOF in space were investigated in this paper. Firstly, the kinematics analysis was developed based on the pseudo-rigid body model. The Jacobian matrix and the relationship between the micro angular deformation of the flexible spherical hinge and the end pose of mobile platform were respectively obtained by employing vector closed-loop method and coordinate transformation method. Then, taking into account the elastic strain energy of the flexible spherical hinge, dynamic model of this mechanism was established via Lagrange equations, and the expression of natural frequency was further derived. Combined with a set of given parameters, natural frequencies of the system were calculated by using MATLAB software. For the comparison purpose, a simulated modal analysis of the mechanism with the same parameters was also performed by employing finite element ANSYS software. Results from numerical calculation and finite element simulation indicated that maximum error of their natural frequencies was 2.71%, which verified the correctness of the theoretical dynamic model. Finally, variations of natural frequencies with changes of the basic parameters were analyzed. Analysis results show that natural frequencies increase with the increase of the bending stiffness of flexible spherical hinge and the difference in radius between static platform and mobile platform, while decrease with the increase of the length of the link rod and the masses of the main components of mechanism. Besides, it can be further drawn from these obtained results that the natural frequencies increase with the increase of the angle between the link rod and the axis of reference coordinate system. Considering that the increase of the stiffness and the angle will reduce the scope of working space, it is recommended in designing the structure to choose a set of larger stiffness and angle as much as possible under the premise of satisfying the working space.
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http://dx.doi.org/10.3390/mi12060678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228077PMC
June 2021

Dysregulation of iron metabolism in cardiovascular diseases: From iron deficiency to iron overload.

Biochem Pharmacol 2021 Aug 23;190:114661. Epub 2021 Jun 23.

Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Iron deficiency and iron overload are the most prevalent and opposite forms of dysregulated iron metabolism that affect approximately 30 percent of the world population, in particularly, elderly and patients with chronic diseases. Both iron deficiency and overload are frequently observed in a wide range of cardiovascular diseases, contributing to the onset and progression of these diseases. One of the devastating seqeulae for iron overload is the induction of ferroptosis, a newly defined form of regulated cell death which heavily impacts cardiac function through ferroptotic cell death in cardiomyocytes. In this review, we will aim to evaluate iron deficiency and iron overload in cardiovascular diseases. We will summarize current therapeutic strategies to tackle iron deficiency and iron overload, major pitfalls of current studies, and future perspectives.
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http://dx.doi.org/10.1016/j.bcp.2021.114661DOI Listing
August 2021

A chitosan/mesoporous silica nanoparticle-based anticancer drug delivery system with a "tumor-triggered targeting" property.

Int J Biol Macromol 2021 Jul 7;183:2017-2029. Epub 2021 Jun 7.

Ministry-of-Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei Key Laboratory of Polymer Materials, Hubei University, Wuhan 430062, China. Electronic address:

To enhance drug utilization and reduce their side effects, the strategy of "tumor-triggered targeting" was introduced to fabricate dual-pH-sensitive chitosan (CHI)/mesoporous silica nanoparticle (MSN)-based anticancer drug delivery system (DDS) in this work. Model drug doxorubicin hydrochloride (DOX) was loaded in MSN, which was modified with benzimidazole (Bz) group. Then chitosan-graft-β-cyclodextrin (CHI-g-CD) was applied as the "gatekeeper" to cover MSN through host-guest interaction between β-CD and Bz. After being coated with targeting peptide adamantane-glycine-arginine-glycine-aspartic acid-serine (Ad-GRGDS), methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) was finally grafted on CHI through the pH-sensitive benzoic imine bond. Due to the dynamic protection of PEG, the obtained carriers were "stealthy" at pH 7.4, but could reveal the shielded targeting peptide and the positive charge of CHI in the weakly acidic environment achieved a "tumor-triggered targeting". Inside cancer cells, the interaction between β-CD and Bz group could be destroyed due to the lower pH, resulted in DOX release. Both in vitro and in vivo studies proved the DDS could targeting induce cancer cell apoptosis, inhibit tumor growth, and reduce the cytotoxicity of DOX against normal cells. It is expected that the system named [email protected] could be a potential choice for cancer therapy.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.06.004DOI Listing
July 2021

Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control.

Theranostics 2021 3;11(14):6766-6785. Epub 2021 May 3.

Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.

Endothelial cells (ECs) constitute the innermost layer in all blood vessels to maintain the structural integrity and microcirculation function for coronary microvasculature. Impaired endothelial function is demonstrated in various cardiovascular diseases including myocardial infarction (MI), which is featured by reduced myocardial blood flow as a result of epicardial coronary obstruction, thrombogenesis, and inflammation. In this context, understanding the cellular and molecular mechanisms governing the function of coronary ECs is essential for the early diagnosis and optimal treatment of MI. Although ECs contain relatively fewer mitochondria compared with cardiomyocytes, they function as key sensors of environmental and cellular stress, in the regulation of EC viability, structural integrity and function. Mitochondrial quality control (MQC) machineries respond to a broad array of stress stimuli to regulate fission, fusion, mitophagy and biogenesis in mitochondria. Impaired MQC is a cardinal feature of EC injury and dysfunction. Hence, medications modulating MQC mechanisms are considered as promising novel therapeutic options in MI. Here in this review, we provide updated insights into the key role of MQC mechanisms in coronary ECs and microvascular dysfunction in MI. We also discussed the option of MQC as a novel therapeutic target to delay, reverse or repair coronary microvascular damage in MI. Contemporary available MQC-targeted therapies with potential clinical benefits to alleviate coronary microvascular injury during MI are also summarized.
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http://dx.doi.org/10.7150/thno.60143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171103PMC
August 2021

Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment.

PLoS One 2021 3;16(6):e0252522. Epub 2021 Jun 3.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, United States of America.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252522PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174701PMC
June 2021

Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth.

Reprod Sci 2021 Jun 2. Epub 2021 Jun 2.

Center of Prenatal Diagnosis, Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, 17 South Renmin Road, Chengdu, China.

Methylmalonic acidemia combined with homocysteinemia and cobalamin C type (MMA-CblC, MIM # 277400) is a rare inherited disease with cobalamin metabolic disorder, which are caused by deficiency in the MMACHC gene. A couple with a proband child carried with compound heterozygous mutations of MMACHC (c.609G>A and c.567 dup T, NM_015506) sought for assisted reproductive technology to avoid the transmission of pathogenic genetic variants and unnecessary induction of labor. Thus, in vitro fertilization (IVF), preimplantation genetic testing (PGT), and prenatal genetic diagnosis were applied to fulfill this clinical demand. In this study, seven embryos were biopsied and carried out whole-genome amplification using multiple annealing and looping-based amplification cycle (MALBAC) method. Sanger sequencing together with copy number variation (CNV) analysis and single-nucleotide polymorphism (SNP) haplotyping was conducted to detect the mutated alleles and chromosomal abnormalities simultaneously. Three embryos (E07, E06, and E02) were confirmed without CNVs and inherited mutations at MMACHC gene. Embryo E07 with the best embryo ranking of 5BB was selected preferentially to transfer which led to a successful pregnancy and an unaffected live birth. Prenatal genetic diagnosing with amniotic fluid cells, Sanger sequencing with cord blood cells, and neonate MMA screening further verified our successful application of PGT in preventing mutated allele transmission for this rare inherited disease.
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http://dx.doi.org/10.1007/s43032-021-00621-3DOI Listing
June 2021

Interfacial Binding Energy between Calcium-Silicate-Hydrates and Epoxy Resin: A Molecular Dynamics Study.

Polymers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Guangdong Provincial Key Laboratory of Durability for Marine Civil Engineering, College of Civil and Transportation Engineering, Shenzhen University, Shenzhen 518060, China.

Microcapsules encapsulated within epoxy as a curing agent have been successfully applied in self-healing materials, in which the healing performance significantly depends on the binding behaviour of the epoxy curing agent with the cement matrix. In this paper, the binding energy was investigated by molecular dynamics simulation, which could overcome the shortcomings of traditional microscopic experimental methods. In addition to the construction of different molecular models of epoxy, curing agents, and dilutants, seven models were established to investigate the effects of chain length, curing agent, and epoxy resin chain direction on the interfacial binding energy. The results showed that an increase of chain length exhibited had limited effect on the binding energy, while the curing agent and the direction of the epoxy significantly affected the interfacial binding energy. Among different factors, the curing agent tetrethylenepentamine exhibited the highest value of interfacial binding energy by an increment of 31.03 kcal/mol, indicating a better binding ability of the microcapsule core and the cement matrix. This study provides a microscopic insight into the interface behaviour between the microcapsule core and the cement matrix.
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http://dx.doi.org/10.3390/polym13111683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196693PMC
May 2021

Orientational Alignment of Oxygen Vacancies: Electric-Field-Inducing Conductive Channels in TiO Film to Boost Photocatalytic Conversion of CO into CO.

Nano Lett 2021 Jun 1;21(12):5060-5067. Epub 2021 Jun 1.

National Laboratory of Solid State Microstructures and Jiangsu Provincial Key Laboratory for Nanotechnology, School of Physics, Nanjing University, Nanjing 210093, People's Republic of China.

Oxide semiconductors are widely used in the photocatalytic fields, and introducing oxygen vacancies is an effective strategy to improve their photocatalytic efficiency. However, oxygen vacancies in the bulk often act as the recombination centers of electron-hole pairs, which accelerates the recombination of electron-hole pairs. In this paper, we propose a strategy of electric field treatment and apply it to a TiO film with oxygen vacancies to promote the photocatalytic efficiency. After treatment by an electric field, the conductive channels consisting of oxygen vacancies are formed in the TiO film, which greatly decreases the resistance by almost 6 × 10 times. The yield of CO can reach up to 1.729 mmol g h, which is one of the best performances among the reported TiO-based catalysts. This work provides an effective and feasible way for enhancing photocatalytic activity through an electric field, and this method is promising for wide use in the field of catalysis.
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http://dx.doi.org/10.1021/acs.nanolett.1c00897DOI Listing
June 2021

A Nomogram for Predicting Multiple Metastases in Metastatic Colorectal Cancer Patients: A Large Population-Based Study.

Front Oncol 2021 13;11:633995. Epub 2021 May 13.

Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, China.

Objectives: The present study aims to discover the risk factors of multiple metastases and develop a functional nomogram to forecast multiple metastases in metastatic colorectal cancer (mCRC) patients.

Methods: mCRC cases were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. Survival times between multiple metastases and single metastasis were compared using Kaplan-Meier analysis and log-rank tests. Risk factors for multiple metastases were determined by univariate and multivariate logistic regression analyses, and a nomogram was developed to forecast the probability of multiple metastases in mCRC patients. We assessed the nomogram performance in terms of discrimination and calibration, including concordance index (C-index), area under the curve (AUC), and decision curve analysis (DCA). Bootstrap resampling was used as an internal verification method, and at the same time we select external data from Renmin Hospital of Wuhan University as independent validation sets.

Results: A total of 5,302 cases were included in this study as training group, while 120 cases were as validation group. The patients with single metastasis and multiple metastases were 3,531 and 1,771, respectively. The median overall survival (OS) and cancer-specific survival (CSS) for patients with multiple metastases or single metastasis were 19 31 months, and 20 33 months, respectively. Based on the univariate and multivariate analyses, clinicopathological characteristics were associated with number of metastasis and were used to establish nomograms to predict the risk of multiple metastases. The C-indexes and AUC for the forecast of multiple metastases were 0.715 (95% confidence interval (CI), 0.707-0.723), which showed the nomogram had good discrimination and calibration curves of the nomogram showed no significant bias from the reference line, indicating a good degree of calibration. In the validation group, the AUC was 0.734 (95% CI, 0.653-0.834), and calibration curve also showed no significant bias, indicating the favorable effects of our nomogram.

Conclusions: We developed a new nomogram to predict the risk of multiple metastases. The nomogram shows the good prediction effect and can provide assistance for clinical diagnosis and treatment.
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http://dx.doi.org/10.3389/fonc.2021.633995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155489PMC
May 2021

ChromInst: A single cell sequencing technique to accomplish pre-implantation comprehensive chromosomal screening overnight.

PLoS One 2021 20;16(5):e0251971. Epub 2021 May 20.

Department of Research and Development, Yikon Genomics (Suzhou) Company Limited, Suzhou, Jiangsu, PR China.

Next Generation Sequencing (NGS) is a powerful tool getting into the field of clinical examination. Its preliminary application in pre-implantation comprehensive chromosomal screening (PCCS) of assisted reproduction (test-tube baby) has shown encouraging outcomes that improves the success rate of in vitro fertilization. However, the conventional NGS library construction is time consuming. In addition with the whole genome amplification (WGA) procedure in prior, makes the single cell NGS assay hardly be accomplished within an adequately short turnover time in supporting fresh embryo implantation. In this work, we established a concise single cell sequencing protocol, ChromInst, in which the single cell WGA and NGS library construction were integrated into a two-step PCR procedure of ~ 2.5hours reaction time. We then validated the feasibility of ChromInst for overnight PCCS assay by examining 14 voluntary donated embryo biopsy samples in a single sequencing run of Miseq with merely 13M reads production. The good compatibility of ChromInst with the restriction of Illumina sequencing technique along with the good library yield uniformity resulted superior data usage efficiency and reads distribution evenness that ensures precisely distinguish of 6 normal embryos from 8 abnormal one with variable chromosomal aneuploidy. The superior succinctness and effectiveness of this protocol permits its utilization in other time limited single cell NGS applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251971PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136696PMC
May 2021

Ferritinophagy and ferroptosis in the management of metabolic diseases.

Trends Endocrinol Metab 2021 07 15;32(7):444-462. Epub 2021 May 15.

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address:

Ferroptosis is a form of regulated cell death modality associated with disturbed iron-homeostasis and unrestricted lipid peroxidation. Ample evidence has depicted an essential role for ferroptosis as either the cause or consequence for human diseases, denoting the likely therapeutic promises for targeting ferroptosis in the preservation of human health. Ferritinophagy, a selective form of autophagy, contributes to the initiation of ferroptosis through degradation of ferritin, which triggers labile iron overload (IO), lipid peroxidation, membrane damage, and cell death. In this review, we will delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of ferritinophagy as a target in the combat of ferroptosis to manage metabolic diseases.
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http://dx.doi.org/10.1016/j.tem.2021.04.010DOI Listing
July 2021

Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.

Nat Commun 2021 05 11;12(1):2582. Epub 2021 May 11.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
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http://dx.doi.org/10.1038/s41467-021-22885-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113440PMC
May 2021

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation.

Int J Radiat Oncol Biol Phys 2021 10 8;111(2):479-490. Epub 2021 May 8.

Department of Surgery, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

Methods And Materials: The study population consisted of children (n = 83, aged 3~18) with primary brain tumors (medulloblastoma, glioma, germ cell tumors (GCT), and central nervous system embryonal tumor-not otherwise specified), with or without residual or disseminated (R/D) diseases who were starting standard postoperative focal or craniospinal irradiation (CSI). Peripheral blood T lymphocyte subsets collected before and 4 weeks after RT were enumerated by flow cytometry. Plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A were measured by cytometric bead array.

Results: Patients with R/D lesions receiving CSI (n = 32) had a post-RT increase in the frequency of CD3+T and CD8+T cells, a decrease in CD4+T cells, and an increase in regulatory T cells (Tregs) and CD8+CD28- suppressor cells, which was more predominantly seen in these patients than in other groups. In the CSI group with such R/D lesions, consisting of patients with medulloblastoma and germ cell tumors, 19 experienced a complete response (CR) and 13 experienced a partial response (PR) on imaging at 4 weeks after RT. The post/pre-RT ratio of Tregs (P = .0493), IL-6 (P = .0111), and IL-10 (P = .0070) was lower in the CR group than in the PR group. Multivariate analysis revealed that the post/pre-RT ratios of Treg, IL-6, and IL-10 were independent predictors of CR (P < .0001, P = .018, P < .0001, respectively). The areas under the receiver operating curves and confidence intervals were 0.7652 (0.5831-0.8964), 0.7794 (0.5980-0.9067), and 0.7085 (0.5223-0.8552) for IL-6, IL-10, and Treg, respectively. The sensitivities of IL-6, IL-10, and Treg to predict radiotherapeutic responses were 100%, 92.3%, and 61.5%, and specificity was 52.6%, 57.9%, and 84.2%, respectively.

Conclusions: CSI treatment to those with R/D lesions predominantly exerted an effect on antitumor immune response compared with both R/D lesion-free but exposed to focal or CSI RT and with R/D lesions and exposed to focal RT. Such CSI with R/D lesions group experiencing CR is more likely to have a decrease in immunoinhibitory molecules and cells than patients who only achieve PR. Measuring peripheral blood Treg, IL-6, and IL-10 levels could be valuable for predicting radiotherapeutic responses of pediatric brain tumors with R/D lesions to CSI for medulloblastoma and intracranial germ cell tumors.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.041DOI Listing
October 2021

Gestational high-fat diet impaired demethylation of Pparα and induced obesity of offspring.

J Cell Mol Med 2021 06 6;25(12):5404-5416. Epub 2021 May 6.

The Key Laboratory of Reproductive Genetics (Zhejiang University School of Medicine), Ministry of Education, Hangzhou, China.

Gestational and postpartum high-fat diets (HFDs) have been implicated as causes of obesity in offspring in later life. The present study aimed to investigate the effects of gestational and/or postpartum HFD on obesity in offspring. We established a mouse model of HFD exposure that included gestation, lactation and post-weaning periods. We found that gestation was the most sensitive period, as the administration of a HFD impaired lipid metabolism, especially fatty acid oxidation in both foetal and adult mice, and caused obesity in offspring. Mechanistically, the DNA hypermethylation level of the nuclear receptor, peroxisome proliferator-activated receptor-α (Pparα), and the decreased mRNA levels of ten-eleven translocation 1 (Tet1) and/or ten-eleven translocation 2 (Tet2) were detected in the livers of foetal and adult offspring from mothers given a HFD during gestation, which was also associated with low Pparα expression in hepatic cells. We speculated that the hypermethylation of Pparα resulted from the decreased Tet1/2 expression in mothers given a HFD during gestation, thereby causing lipid metabolism disorders and obesity. In conclusion, this study demonstrates that a HFD during gestation exerts long-term effects on the health of offspring via the DNA demethylation of Pparα, thereby highlighting the importance of the gestational period in regulating epigenetic mechanisms involved in metabolism.
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http://dx.doi.org/10.1111/jcmm.16551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184666PMC
June 2021
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