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1.
Lab Chip ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33616124

RESUMO

A microfluidics-based three-dimensional skin-on-chip (SoC) model is developed in this study to enable quantitative studies of transendothelial and transepithelial migration of human T lymphocytes in mimicked skin inflammatory microenvironments and to test new drug candidates. The keys results include 1) CCL20-dependent T cell transmigration is significantly inhibited by an engineered CCL20 locked dimer (CCL20LD), supporting the potential immunotherapeutic use of CCL20LD for treating skin diseases such as psoriasis; 2) transepithelial migration of T cells in response to a CXCL12 gradient mimicking T cell egress from the skin is significantly reduced by a sphingosine-1-phosphate (S1P) background, suggesting the role of S1P for T cell retention in inflamed skin tissues; and 3) T cell transmigration is induced by inflammatory cytokine stimulated epithelial cells in the SoC model. Collectively, the developed SoC model recreates a dynamic multi-cellular micro-environment that enables quantitative studies of T cell transmigration at a single cell level in response to physiological cutaneous inflammatory mediators and potential drugs.

2.
Dev Cogn Neurosci ; 48: 100918, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33571846

RESUMO

Little is known about the neural processes associated with attending to social stimuli during infancy and toddlerhood. Using infant magnetoencephalography (MEG), fusiform gyrus (FFG) activity while processing Face and Non-Face stimuli was examined in 46 typically developing infants 3 to 24 months old (28 males). Several findings indicated FFG maturation throughout the first two years of life. First, right FFG responses to Face stimuli decreased as a function of age. Second, hemispheric specialization to the face stimuli developed somewhat slowly, with earlier right than left FFG peak activity most evident after 1 year of age. Right FFG activity to Face stimuli was of clinical interest, with an earlier right FFG response associated with better performance on tests assessing social and cognitive ability. Building on the above, clinical studies examining maturational change in FFG activity (e.g., lateralization and speed) in infants at-risk for childhood disorders associated with social deficits are of interest to identify atypical FFG maturation before a formal diagnosis is possible.

3.
J Orthop Surg Res ; 16(1): 158, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632253

RESUMO

BACKGROUND: This study was done to observe the incidence of Osteo-line on the femur neck and to explore the clinical application of Osteo-line in osteotomy. METHODS: Eighty-nine adult femur specimens were selected to observe the incidence of Osteo-line on the femur neck. From August 2015 to January 2019, a total of 278 patients who completed unilateral hip arthroplasty at the Third Hospital of Hebei Medical University were retrospectively included. Patients who accepted osteotomy via Osteo-line on the femur neck were defined as the experimental group (n = 139), and patients who accepted osteotomy via traditional method (The femoral distance 1.5 cm above the trochanter was retained for osteotomy by visual inspection.) were defined as the control group (n = 139). According to the postoperative pelvic X-ray, Photoshop was used to evaluate the leg length discrepancy (LLD) by the CFR-T-LT method. RESULTS: Among the 89 specimens, the incidence of anterior Osteo-line was 75.28%, and the incidence of posterior Osteo-line was 100%. According to the clinical application results, the incidence of anterior Osteo-line on the femur neck was 80%, and the incidence of posterior Osteo-line was 100%. The Osteo-line was clearer than those on the femoral specimens. Twenty-six cases had LLD greater than 1 cm (9.29%), including 2 cases in the experimental group and 24 cases in the control group. The average postoperative LLD in the experimental group (0.19 ± 0.38 mm) was significantly shorter than in the control group (0.54 ± 0.51 mm)(P = 0.005). CONCLUSION: The incidence of Osteo-line on the femur neck was high, and patients who accepted osteotomy via Osteo-line on the femur neck can achieve shorter postoperative LLD than the control group.

4.
J Autism Dev Disord ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33629214

RESUMO

Associations between age, resting-state (RS) peak-alpha-frequency (PAF = frequency showing largest amplitude alpha activity), and thalamic volume (thalamus thought to modulate alpha activity) were examined to understand differences in RS alpha activity between children with autism spectrum disorder (ASD) and typically-developing children (TDC) noted in prior studies. RS MEG and structural-MRI data were obtained from 51 ASD and 70 TDC 6- to 18-year-old males. PAF and thalamic volume maturation were observed in TDC but not ASD. Although PAF was associated with right thalamic volume in TDC (R2 = 0.12, p = 0.01) but not ASD (R2 = 0.01, p = 0.35), this group difference was not large enough to reach significance. Findings thus showed unusual maturation of brain function and structure in ASD as well as an across-group thalamic contribution to alpha rhythms.

5.
Adv Mater ; : e2004305, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33522035

RESUMO

Silicon waveguides have enabled large-scale manipulation and processing of near-infrared optical signals on chip. Yet, expanding the bandwidth of guided waves to other frequencies will further increase the functionality of silicon as a photonics platform. Frequency multiplexing by integrating additional architectures is one approach to the problem, but this is challenging to design and integrate within the existing form factor due to scaling with the free-space wavelength. This paper demonstrates that a hexagonal boron nitride (hBN)/silicon hybrid waveguide can simultaneously enable dual-band operation at both mid-infrared (6.5-7.0 µm) and telecom (1.55 µm) frequencies, respectively. The device is realized via the lithography-free transfer of hBN onto a silicon waveguide, maintaining near-infrared operation. In addition, mid-infrared waveguiding of the hyperbolic phonon polaritons (HPhPs) supported in hBN is induced by the index contrast between the silicon waveguide and the surrounding air underneath the hBN, thereby eliminating the need for deleterious etching of the hyperbolic medium. The behavior of HPhP waveguiding in both straight and curved trajectories is validated within an analytical waveguide theoretical framework. This exemplifies a generalizable approach based on integrating hyperbolic media with silicon photonics for realizing frequency multiplexing in on-chip photonic systems.

6.
Cancer Imaging ; 21(1): 20, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33549151

RESUMO

BACKGROUND: We sought to evaluate the performance of a computed tomography (CT)-based radiomics nomogram we devised in distinguishing benign from malignant bone tumours. METHODS: Two hundred and six patients with bone tumours were spilt into two groups: a training set (n = 155) and a validation set (n = 51). A feature extraction process based on 3D Slicer software was used to extract the radiomics features from unenhanced CT images, and least absolute shrinkage and selection operator logistic regression was used to calculate the radiomic score to generate a radiomics signature. A clinical model comprised demographics and CT features. A radiomics nomogram combined with the clinical model and the radiomics signature was constructed. The performance of the three models was comprehensively evaluated from three aspects: identification ability, accuracy, and clinical value, allowing for generation of an optimal prediction model. RESULTS: The radiomics nomogram comprised clinical and radiomics signature features. The nomogram model displayed good performance in training and validation sets with areas under the curve of 0.917 and 0.823, respectively. The areas under the curve, decision curve analysis, and net reclassification improvement showed that the radiomics nomogram model could obtain better diagnostic performance than the clinical model and achieve greater clinical net benefits than the clinical and radiomics signature models alone. CONCLUSIONS: We constructed a combined nomogram comprising a clinical model and radiomics signature as a noninvasive preoperative prediction method to distinguish between benign and malignant bone tumours and assist treatment planning.

7.
Eur Radiol ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33569616

RESUMO

OBJECTIVES: To summarise the CT findings of gastric poorly cohesive carcinoma (PCC) in the 40 s late arterial phase and differentiate it from tubular adenocarcinoma (TAC) using an integrative nomogram. METHODS: A total of 241 patients including 59 PCCs, 109 TACs, and 73 other type gastric cancers were enrolled. Thirteen CT morphological characteristics of each lesion in the late arterial phase were evaluated. In addition, CT value-related parameters were extracted from ROIs encompassing the area of greatest enhancement on four-phase CT images. Nomograms based on regression models were built to discriminate PCCs from TACs and from non-PCCs. ROC curve analysis was performed to assess the diagnostic efficiency. RESULTS: Six morphological characteristics, 10 CT value-related parameters, and the enhanced curve types differed significantly among the above three groups in the primary cohort (all p < 0.05). The paired comparison revealed that 10 CT value-related parameters differed significantly between PCCs and TACs (all p < 0.05). The AUC of the nomogram based on the multivariate model for discriminating PCCs from TACs was 0.954, which was confirmed in the validation cohort (AUC = 0.895). The AUC of another nomogram for discriminating PCCs from non-PCCs was 0.938, which was confirmed in the validation cohort (AUC = 0.880). CONCLUSIONS: In the 40 s late arterial phase, the morphological characteristics and CT value-related parameters were significantly different among PCCs, TACs, and other types. PCCs were prone to manifest mucosal line interruption, diffuse thickening, infiltrative growth, and slow-rising enhanced curve (Type A). Furthermore, multivariate models were useful in discriminating PCCs from TACs and other types. KEY POINTS: • Multiple morphological characteristics and CT value-related parameters differed significantly between gastric PCCs and TACs in the 40 s late arterial phase. • The nomogram integrating morphological characteristics and CT value-related parameters in the 40 s late arterial phase had favourable performance in discriminating PCCs from TACs. • More useful information can be derived from 40 s late arterial phase CT images; thus, a more accurate evaluation can be made in clinical practice.

8.
Eur Radiol ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33566147

RESUMO

OBJECTIVES: There is close relationship between lenticulostriate arteries (LSAs) and lacunar infarctions (LIs) of the basal ganglia. The study aims to visualize the LSAs using high-resolution vessel wall imaging (VWI) on 3T system and explore the correlation between LSAs and LIs. METHODS: Fifty-six patients with LIs in basal ganglia, and 44 age-matched control patients were enrolled and analyzed retrospectively. The raw VWI images were reformatted into coronal slices in minimum intensity projection for further observation of LSAs. The risk factors of LIs in basal ganglia were analyzed by univariate and multivariate logistic regression. The correlation and linear regression analysis between the LSAs and LIs, ipsilateral MCA-M1 plaques were investigated. RESULTS: The total number (p < 0.01) and length (p < 0.01) of LSAs were statistically different between basal ganglias with and without LIs. The total number of LSAs and ipsilateral MCA-M1 plaques were independently related to LIs in basal ganglias. The mean length of LSAs were negatively correlated with number (r = - 0.33, p = 0.002) and volume (r = - 0.37, p = 0.001) of LIs. Age, drinking history, and mean length of LSAs were associated with LI occurrence in basal ganglia, and mean length of LSAs was correlated with larger volume of LIs. CONCLUSIONS: Number of LSA reduction and ipsilateral MCA-M1 plaques were associated with the presence of LIs in basal ganglias. Age increasing, drinking history, and shorter LSAs were correlated with the increasing of LIs. KEY POINTS: • Patients with LIs tend to have shorter LSAs. • The characteristics of LSAs and ipsilateral MCA-M1 plaques are associated with LIs in basal ganglias. • Age, drinking history, and mean length of LSAs are correlated with LI features in basal ganglias.

9.
Childs Nerv Syst ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33559728

RESUMO

PURPOSE: Cerebral palsy (CP) is the most common neuromuscular disease in children, and currently, there is no cure. Several studies have reported the benefits of umbilical cord blood (UCB) cell treatment for CP. However, these studies either examined the effects of UCB cell fraction with a short experimental period or used neonatal rat models for a long-term study which displayed an insufficient immunological reaction and clearance of human stem cells. Here, we developed a CP model by hypoxia-ischemic injury (HI) using immunodeficient mice and examined the effects of human UCB CD34+ hematopoietic stem cells (HSCs) on CP therapy over a period of 8 weeks. METHODS: Sixty postnatal day-9 (P9) mouse pups were randomly divided into 4 groups (n = 15/group) as follows: (1) sham operation (control group), (2) HI-induced CP model, (3) CP model with CD34+ HSC transplantation, and (4) CP model with CD34- cell transplantation. Eight weeks after insult, the sensorimotor performance was analyzed by rotarod treadmill, gait dynamic, and open field assays. The pathological changes in brain tissue of mice were determined by HE staining, Nissl staining, and MBP immunohistochemistry of the hippocampus in the mice. RESULTS: HI brain injury in mice pups resulted in significant behavioral deficits and loss of neurons. Both CD34+ HSCs and CD34- cells improved the neurobehavioral statuses and alleviated the pathological brain injury. In comparison with CD34- cells, the CD34+ HSC compartments were more effective. CONCLUSION: These findings indicate that CD34+ HSC transplantation was neuroprotective in neonatal mice and could be an effective therapy for CP.

10.
Sci Adv ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523857

RESUMO

In ultraviolet (UV) radiation-exposed skin, mutations fuel clonal cell growth. The relationship between UV exposure and the accumulation of clonal mutations (CMs) and the correlation between CMs and skin cancer risk are largely unexplored. We characterized 450 individual-matched sun-exposed (SE) and non-SE (NE) normal human skin samples. The number and relative contribution of CMs were significantly different between SE and NE areas. Furthermore, we identified hotspots in TP53, NOTCH1, and GRM3 where mutations were significantly associated with UV exposure. In the normal skin from patients with cutaneous squamous cell carcinoma, we found that the cancer burden was associated with the UV-induced mutations, with the difference mostly conferred by the low-frequency CMs. These findings provide previously unknown information on UV's carcinogenic effect and pave the road for future development of quantitative assessment of subclinical UV damage and skin cancer risk.

11.
Medicine (Baltimore) ; 100(3): e24365, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546073

RESUMO

ABSTRACT: Percutaneous ethanol injection is a well-known ablation therapy for hepatocellular carcinoma and is well-tolerated, inexpensive, and effective with few adverse events. In this study, another type of ethanol injection was introduced in the present study.Sixty two patients with hepatocellular carcinoma received 133 percutaneous peritumor ethanol injection treatments and the 15-year follow-up outcomes were analyzed through a collected database.The technical efficiency was 89.5% (119/133 treatments) after the first percutaneous peritumor ethanol injection procedure. However, after the second repeated percutaneous peritumor ethanol injection procedure, technical efficiency increased to 98.5% (131/133 treatments). The 1 year, 3 years, 5 years, 10 years, and 15 years rates of tumor recurrence were 12.9%, 50.0%, 59.7%, 74.2%, and 74.2%, respectively. Multivariate analysis demonstrated that diabetes, Child-Pugh class B, and tumor size greater than 2 cm were significantly related to tumor recurrence. The 1 year, 3 years, 5 years, 10 years, and 15 years rates of overall survival were 98.4%, 83.6%, 61.3%, 19.4%, and 0%, respectively. Multivariate analysis demonstrated that Child-Pugh class B, tumor size greater than 2 cm, and multiple tumors were significantly related to overall survival.Compared with other ablation methods (including peritumor ethanol injection), percutaneous peritumor ethanol injection can avoid tumor ruptures, reduce tumor proliferation and metastasis, and is suitable for the treatment of small tumors. In addition, when combined with other treatment methods, percutaneous peritumor ethanol injection can form a tumor metastatic isolation zone in advance and improve the comprehensive treatment effect.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Etanol/uso terapêutico , Idoso , Carcinoma Hepatocelular/complicações , Feminino , Seguimentos , Humanos , Injeções Intralesionais/métodos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
12.
Proc Natl Acad Sci U S A ; 118(8)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33602823

RESUMO

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

13.
Nature ; 590(7844): 80-84, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33536650

RESUMO

Active matter consists of units that generate mechanical work by consuming energy1. Examples include living systems (such as assemblies of bacteria2-5 and biological tissues6,7), biopolymers driven by molecular motors8-11 and suspensions of synthetic self-propelled particles12-14. A central goal is to understand and control the self-organization of active assemblies in space and time. Most active systems exhibit either spatial order mediated by interactions that coordinate the spatial structure and the motion of active agents12,14,15 or the temporal synchronization of individual oscillatory dynamics2. The simultaneous control of spatial and temporal organization is more challenging and generally requires complex interactions, such as reaction-diffusion hierarchies16 or genetically engineered cellular circuits2. Here we report a simple technique to simultaneously control the spatial and temporal self-organization of bacterial active matter. We confine dense active suspensions of Escherichia coli cells and manipulate a single macroscopic parameter-namely, the viscoelasticity of the suspending fluid- through the addition of purified genomic DNA. This reveals self-driven spatial and temporal organization in the form of a millimetre-scale rotating vortex with periodically oscillating global chirality of tunable frequency, reminiscent of a torsional pendulum. By combining experiments with an active-matter model, we explain this behaviour in terms of the interplay between active forcing and viscoelastic stress relaxation. Our findings provide insight into the influence of bacterial motile behaviour in complex fluids, which may be of interest in health- and ecology-related research, and demonstrate experimentally that rheological properties can be harnessed to control active-matter flows17,18. We envisage that our millimetre-scale, tunable, self-oscillating bacterial vortex may be coupled to actuation systems to act a 'clock generator' capable of providing timing signals for rhythmic locomotion of soft robots and for programmed microfluidic pumping19, for example, by triggering the action of a shift register in soft-robotic logic devices20.

14.
Int Urol Nephrol ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387225

RESUMO

PURPOSE: Clinical classification of hyperuricemia (HUA) could help to guide therapy of HUA. Studies on the classification of HUA with chronic kidney disease (CKD) are rare. Therefore, we aimed to investigate the classification of HUA with CKD. METHODS: A cross-sectional study of 428 CKD patients was conducted, including 218 HUA patients. By correlation analysis, the association of 24-h urinary uric acid (24-h Uur), uric acid clearance rate (Cur), the urinary uric acid excretion per kilogram of weight per hour (Eur) and fractional excretion of uric acid (FEur) with estimated glomerular filtration rate (eGFR) was analyzed in the HUA and non-HUA groups. According to Eur combined with Cur and the 24-h Uur combined with FEur, HUA with CKD was classified into underexcretion, renal overload, combined and 'normal' types, which were also stratified by CKD stages. RESULTS: According to the Eur and Cur, in early CKD (eGFR ≥ 60 mL/min/1.73 m2), the underexcretion type accounted for 83.75%, and the renal overload type accounted for 2.5%. As the CKD stage increased, the proportion of the underexcretion type increased. According to the 24-h Uur and FEur, in early CKD, the underexcretion type accounted for 53.75%, and the renal overload type accounted for 15%. With increasing CKD stages, the proportion of the 'normal' type increased significantly. CONCLUSION: Different uses of Eur with Cur or 24-h Uur with FEur varied significantly in classifying HUA patients with CKD. Eur + Cur may be more applicable to the classification of HUA patients with CKD, and further research is needed.

15.
Analyst ; 146(4): 1369-1375, 2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33393557

RESUMO

The tetrazole-based photoclick chemistry has attracted considerable attention in virtue of its good biocompatibility, exclusive molecular reaction, and spatiotemporally controllable properties. Using this photoclick reaction, we designed an in situ, real-time fluorescence imaging system that targeted mitochondria and lysosomes in a spatiotemporally controllable manner. Upon irradiation, the pyrazoline fluorophore was generated in situ by the intramolecular tetrazole-alkene cycloaddition reaction ("photo-click chemistry"). This strategy exhibits features such as fast response, high efficiency, strong fluorescence intensity without background and superior stability. In addition, by integrating with an organelle-specific group, it has a good application for subcellular targeting imaging. Furthermore, the photo-responsive moiety Tet facilitates the probes, Mt-Tet and Ly-Tet, for the super-resolution imaging of subcellular structures.

16.
ACS Synth Biol ; 10(2): 265-276, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33464830

RESUMO

Synonymous mutation of the N-terminal coding sequence (NCS) has been used to regulate gene expression. We here developed a statistical model to predict the effect of the NCSs on protein expression in Bacillus subtilis WB600. First, a synonymous mutation was performed within the first 10 residues of a superfolder green fluorescent protein to generate a library of 172 NCS synonymous mutants with different expression levels. A prediction model was then developed, which adopted G/C frequency at the third position of each codon and minimum free energy of mRNA as the independent variables, using multiple regression analysis between the 11 sequence parameters of the NCS and their fluorescence intensities. By designing the NCS of the 10 signal peptides de novo according to the model, the extracellular yield of B. subtilis pullulanase fused to each signal peptide was up-regulated by up to 515% or down-regulated by at most 79%. This work provided a candidate tool for fine-tuning gene expression or enzyme production in B. subtilis.

17.
Acad Radiol ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33487536

RESUMO

RATIONALE AND OBJECTIVES: To develop and validate multivariate models integrating endoscopic biopsy, tumor markers, computed tomography (CT) morphological characteristics based on late arterial phase (LAP), and CT value-related and texture parameters to predict lymph node (LN) metastasis in gastric cancers (GCs). MATERIALS AND METHODS: The preoperative differentiation degree based on biopsy, 6 tumor markers, 8 CT morphological characteristics based on LAP, 18 CT value-related parameters, and 35 CT texture parameters of 163 patients (111 men and 52 women) with GC were analyzed retrospectively. The differences in parameters between N (-) and N (+) GCs were analyzed by the Mann-Whitney U test. Diagnostic performance was obtained by receiver operating characteristic (ROC) curve analysis. Multivariate models based on regression analysis and machine learning algorithms were performed to improve diagnostic efficacy. RESULTS: The differentiation degree, carbohydrate antigen (CA) 199 and CA242, 5 CT morphological characteristics, and 22 CT texture parameters showed significant differences between N (-) and N (+) GCs in the primary cohort (all p < 0.05). The multivariate model integrating clinicopathological parameters and radiographic findings based on regression analysis achieved areas under the ROC curve (AUCs) of 0.936 and 0.912 in the primary and validation cohorts, respectively. The model generated by the support vector machine algorithm achieved AUCs of 0.914 and 0.948, respectively. CONCLUSION: We developed and validated multivariate models integrating endoscopic biopsy, tumor markers, CT morphological characteristics based on LAP, and CT texture parameters to predict LN metastasis in GCs and achieved satisfactory performance.

18.
J Immunother Cancer ; 9(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33495298

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in 'non-inflamed' or 'cold' tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known. METHODS: Human TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells. RESULTS: Our results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME. CONCLUSIONS: These findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.

19.
Chem Commun (Camb) ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33438691

RESUMO

A series of heterogeneous molecular catalysts by immobilizing nickel(ii) phthalocyanine (NiPc) onto different carbon supports were constructed to study the influence of the catalyst's microstructure on the performance of electrochemical carbon dioxide reduction reaction (CO2RR). The microporous structure of the electrocatalysts could influence CO2 transfer and therefore change the CO2 concentration at the surface of the catalyst, which singnificantly impacted the CO2RR performance.

20.
J Exp Clin Cancer Res ; 40(1): 39, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485379

RESUMO

The stimulator of interferon genes (STING) connects microbial cytosolic sensing with host cell effector functions. STING signaling plays a central role in cyclic dinucleotides (CDNs) and DNA sensing to induce secretion of interferons and pro-inflammatory mediators. Although activated STING signaling favors antimicrobial progress and facilitates mucosal would healing, its role in mucosal immunity and gut homeostasis is paradoxical, ranging from positive and negative effects within the gut. In our review, we summarize recent advance of STING signaling in gut homeostasis and inflammation, especially focusing on its molecular basis in mucosal immune response. Deep understanding of the regulatory mechanisms of intestinal STING pathway could promote clinical manipulation of this fundamental signaling as a promising immunomodulatory therapy.

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