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1.
Anal Chem ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35005885

RESUMO

The two major subtypes of human T cells, CD4+ and CD8+, play important roles in adaptive immune response by their diverse functions. To understand the structure-function relation at the single cell level, we isolated 2483 CD4+ and 2450 CD8+ T cells from fresh human splenocytes by immunofluorescent sorting and investigated their morphologic relations to the surface CD markers by acquisition and analysis of cross-polarized diffraction image (p-DI) pairs. A deep neural network of DINet-R has been built to extract 2560 features across multiple pixel scales of a p-DI pair per imaged cell. We have developed a novel algorithm to form a matrix of Pearson correlation coefficients by these features for selection of a support cell set with strong morphologic correlation in each subtype. The p-DI pairs of support cells exhibit significant pattern differences between the two subtypes defined by CD markers. To explore the relation between p-DI features and CD markers, we divided each subtype into two groups of A and B using the two support cell sets. The A groups comprise 90.2% of the imaged T cells and classification of them by DINet-R yields an accuracy of 97.3 ± 0.40% between the two subtypes. Analysis of depolarization ratios further reveals the significant differences in molecular polarizability between the two subtypes. These results prove the existence of a strong structure-function relation for the two major T cell subtypes and demonstrate the potential of diffraction imaging flow cytometry for accurate and label-free classification of T cell subtypes.

2.
Arterioscler Thromb Vasc Biol ; : ATVBAHA121317093, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35021856

RESUMO

BACKGROUND: Endothelial cells (ECs) play a critical role in angiogenesis and vascular remodeling. The heterogeneity of ECs has been reported at adult stages, yet it has not been fully investigated. This study aims to assess the transcriptional heterogeneity of developmental ECs at spatiotemporal level and to reveal the changes of embryonic ECs clustering when endothelium-enriched microRNA-126 (miR-126) was specifically knocked out. METHODS: C57BL/6J mice embryos at day 14.5 were harvested and digested, followed by fluorescence-activated cell sorting to enrich ECs. Then, single-cell RNA sequencing was applied to enriched embryonic ECs. Tie2 (Tek receptor tyrosine kinase)-cre-mediated ECs-specific miR-126 knockout mice were constructed, and ECs from Tie2-cre-mediated ECs-specific miR-126 knockout embryos were subjected to single-cell RNA sequencing. RESULTS: Embryonic ECs were clustered into 11 groups corresponding to anatomic characteristics. The vascular bed (arteries, capillaries, veins, lymphatics) exhibited transcriptomic similarity across the developmental stage. Embryonic ECs had higher proliferative potential than adult ECs. Integrating analysis showed that 3 ECs populations (hepatic, mesenchymal transition, and pulmonary ECs) were apparently disorganized after miR-126 being knocked out. Gene ontology analysis revealed that disrupted ECs were mainly related to hypoxia, glycometabolism, and vascular calcification. Additionally, in vivo experiment showed that Tie2-cre-mediated ECs-specific miR-126 knockout mice exhibited excessive intussusceptive angiogenesis; reductive glucose and pyruvate tolerance; and excessive accumulation of calcium. Agonist miR-126-3p agomir significantly rescued the phenotype of glucose metabolic dysfunction in Tie2-cre-mediated ECs-specific miR-126 knockout mice. CONCLUSIONS: The heterogeneity of ECs is established as early as the embryonic stage. The deficiency of miR-126 disrupts the differentiation and diversification of embryonic ECs, suggesting that miR-126 plays an essential role in the maintenance of ECs heterogeneity.

3.
Cancer Med ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35023616

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR-mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. METHODS: From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer-related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence-free survival (RFS) were analyzed. RESULTS: A total of 637 patients were enrolled in this study. The top three frequent co-mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07-4.00, p = 0.030; HR 3.09, 95% CI 1.49-6.40, p = 0.002, respectively]. CONCLUSIONS: Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR-mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

4.
Neurol Ther ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35006479

RESUMO

INTRODUCTION: This study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of opicapone (OPC) in healthy Chinese and Caucasian subjects. METHODS: In this open-label, single-center, phase 1 study, eligible Chinese subjects received one of three OPC doses (25, 50, or 100 mg), and Caucasian subjects received either 25 or 50 mg of OPC. All subjects were administered a single dose of OPC, whereas subjects in the 50-mg OPC group continued to receive once-daily doses of 50 mg OPC for 10 days. The primary endpoint was to evaluate and compare the plasma concentrations and PK parameters of OPC and its main metabolite, and erythrocyte-soluble catechol-O-methyltransferase (S-COMT) activity in Chinese subjects with that of Caucasian subjects. The secondary endpoint was to evaluate the safety of OPC in Chinese subjects. The estimated results for geometric mean ratios (GMRs) were evaluated with the standard bioequivalence (BE) limits between 80% and 125% to evaluate the ethnic differences. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 70 subjects (45 Chinese, 25 Caucasian) were enrolled; the majority of them were male (85.7%). The plasma exposure of both OPC and BIA 9-1103 increased in an approximately dose-proportional manner in both populations. Maximum S-COMT inhibition ranged from 79% to 95% after a single dose and was about 94% after a 10-day once-daily regimen in both populations. The point estimates of GMRs (Chinese/Caucasian) and 90% CI, except Cmax in 25-mg and 50-mg OPC groups, for PK and PD parameters were within 80% to 125%. Furthermore, no new risks or safety concerns associated with OPC were identified, indicating a tolerable safety profile in healthy Chinese subjects. CONCLUSION: Ethnicity had no significant impact on PK and PD parameters after single or multiple doses of OPC, and OPC was safe and tolerable in healthy Chinese subjects. TRIAL REGISTRATION: ChiCTR number, CTR20192230.

5.
Asian J Androl ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017389

RESUMO

Testosterone production by Leydig cells (LCs) plays a crucial role in male reproduction. The functional degeneration of LCs can cause testosterone deficiency, ultimately resulting in primary male hypogonadism. Transplantation of exogenous LCs with the ability to produce testosterone in response to the regulation of the hypothalamus-pituitary-gonad axis could be a promising alternative option to treat male primary hypogonadism. Recent studies have shown that it is possible to generate Leydig-like cells from stem cells by various approaches. In addition, somatic cells, such as embryonic or adult fibroblasts, have also been successfully reprogrammed into Leydig-like cells. In this review, we summarized the recent advances in the generation of Leydig-like cells, with an emphasis on comparing the effectiveness and safety of different protocols used and the cells generated. By further analyzing the characteristics of Leydig-like cells generated from fibroblasts based on small signaling molecules and regulatory factors, we found that although the cells may produce testosterone, they are significantly different from real LCs. For future in vivo applications, it is important that the steroidogenic cells generated be evaluated not only for their steroidogenic functions but also for their overall cell metabolic state by proteomics or transcriptomic tools.

6.
J Appl Lab Med ; 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35018420

RESUMO

BACKGROUND: Streptavidin-to-biotin binding is one of the strongest noncovalent interactions in nature and incorporated into many immunoassays. Biotin-streptavidin coupling assays are susceptible to interference from free biotin in patient specimens, which may falsely decrease or increase results. To prevent biotin interference, we evaluated a method to preconjugate biotinylated antibodies to the assay's streptavidin solid surface before adding patient specimen and compared this technique to a biotin depletion protocol. METHODS: Biotin interference in 3 manual ELISAs and 2 automated immunoassays was established. Mitigation of biotin interference by preincubation was evaluated in each assay by adding biotinylated antibody to the streptavidin-coated surface before adding biotin- or PBS-spiked serum. Lastly, the preincubation method was compared to a biotin-depletion protocol to compare the effectiveness of mitigating biotin interference. RESULTS: In the presence of 400 µg/L biotin, analyte detection was reduced to 10% to 15% of total in the ELISA assays and to 15.2% in the automated sandwich (thyroglobulin) immunoassay. In the automated competitive (free thyroxine) immunoassay, biotin caused an increased detection of 551.6%. Preconjugation of the biotinylated capture antibody to the streptavidin surface in the ELISA assays resulted in 84% to 99% activity recovery, compared to 84% to 97% by a biotin depletion protocol. Similarly, automated sandwich and competitive immunoassays obtained 97.1% and 116.5% recovery by preconjugation, compared to 95.6% and 100.3% by the depletion method, respectively. CONCLUSION: This study demonstrates how assay redesign to include preconjugation of biotinylated capture antibody to streptavidin is an effective alternative to biotin-depletion methods to mitigate biotin interference.

7.
Artigo em Inglês | MEDLINE | ID: mdl-35031864

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had severe consequences for health and the global economy. To control the transmission, there is an urgent demand for early diagnosis and treatment in the general population. In the present study, an automatic system for SARS-CoV-2 diagnosis is designed and built to deliver high specification, high sensitivity, and high throughput with minimal workforce involvement. The system, set up with cross-priming amplification (CPA) rather than conventional reverse transcription-polymerase chain reaction (RT-PCR), was evaluated using more than 1000 real-world samples for direct comparison. This fully automated robotic system performed SARS-CoV-2 nucleic acid-based diagnosis with 192 samples in under 180 min at 100 copies per reaction in a "specimen in data out" manner. This throughput translates to a daily screening capacity of 800-1000 in an assembly-line manner with limited workforce involvement. The sensitivity of this device could be further improved using a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-based assay, which opens the door to mixed samples, potentially include SARS-CoV-2 variants screening in extensively scaled testing for fighting COVID-19.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34981923

RESUMO

The prosperity of the electric vehicle industry is driving the research and development of lithium-ion batteries. As one of the core components in the entire battery system, cathode materials are currently facing major challenges in pushing a higher capacity up to the materials' theoretical limits and transitioning away from unaffordable metals. The search for next-generation cathode materials has shifted to high-nickel and cobalt-free cathodes to meet these requirements. In this review, we distinctly point out the shortcomings of cobalt in stabilizing layered structures and systematically summarize the recent efforts to eliminate cobalt and achieve higher nickel content in layered cathode materials. Finally, a reasonable prospect is put forward for further development of layered cathode materials and other promising candidates, which is likely to spur a wave of efforts toward developing high-performance and low-cost Li-ion batteries.

9.
Chem Biodivers ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34994077

RESUMO

Methanolic extracts of the leaf and flower of Michelia L., an evergreen aromatic genus widely used in landscaping, industry and medicine of various countries, were analyzed. The UPLC-ESI-MS/MS analysis led to the identification of 28 polyphenols from six Michelia species that widely distributed and cultivated in southern China, among which quinic acid and chlorogenic acid were the main components. The flower extract of Michelia maudiae had the most abundant polyphenols content, as well as high contents of total phenolic (117.31 ± 7.26 mg GAE/g DW) and total flavonoid (251.60 ± 15.56 mg CE/g DW). Meanwhile, it also showed outstanding performance in three antioxidant indexes of DPPH, ABTS and FRAP. The leaf extracts of Michelia chapensis and Michelia floribunda exhibited excellent inhibition against four pathogenic bacteria. Moreover, certain inhibitory activities were displayed by Michelia macclurei extracts against α-amylase and α-glucosidase This study explored the biological activities of six Michelia species, and provided reference for variety selection with the aim of designing novel phyto-pharmaceuticals.

10.
Food Chem ; 370: 131044, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34509940

RESUMO

The shelf life of chestnut rose beverage is largely dependent on packaging method and storage temperature. In this study, we investigated the effects of packaging beverages in bottles made of either polyethylene terephthalate (PET) or PEN (polyethylene naphthalate)/PET and storage temperature (4, 25, 37, and 55 ℃) on the shelf life of chestnut rose beverage. The physicochemical parameters and enzyme activity of beverages were evaluated, and we found that at 4 °C, the vitamin C, superoxide dismutase, and total polyphenol contents of beverages stored in PEN/PET bottles increased by 9.95 ± 0.49%, 2.86 ± 0.13%, and 3.23 ± 0.09% respectively, compared to beverages in ordinary PET bottles. In addition, other characteristic indicators including total soluble solids, browning index, and color value were also significantly improved. A shelf-life model was established based on the Arrhenius equation, and it will help distributors and consumers to determine the storage time and optimal shelf life of chestnut rose beverage.


Assuntos
Polietilenotereftalatos , Rosa , Bebidas/análise , Embalagem de Alimentos , Polietilenotereftalatos/análise , Temperatura
11.
J Colloid Interface Sci ; 610: 182-193, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34922074

RESUMO

In this work, we present an effective approach for promoting the immobilization of anionic dyes on the collagen fibers of the leather matrix via introducing layered double oxide (LDO), which is obtained by calcining layered double hydroxides (LDH), inspired by incorporating their memory effect and charge effect. The results indicate that the calcination increases specific surface area, oxygen vacancies, and Al3+ defects of LDH nanosheets, and the structure of LDH nanosheets can be reconstructed by rehydration. Diffusion behavior of both LDH and LDO nanosheets into the collagen fibers follows the Langmuir model. The LDO nanosheets can penetrate into the collagen fibers more easily and evenly than that of the LDH nanosheets. Moreover, the formation of ionic bonds, hydrogen bonds, and coordination bonds between the nanosheets and the collagen stabilizing the collagen microstructures can endow the collagen fibers with improved thermal stability. Increased porosity of the collagen fibers results in enhanced adsorption and immobilization capacity for anionic dyes on the collagen fibers of the leather matrix in leather post-tanning process. Furthermore, adsorption behavior of anionic dye on the collagen fibers can be well accorded with pseudo-second-order and Langmuir model, exhibiting a monolayer adsorption process. This established cooperative approach will be helpful to extend the application of clay for improving the dyeing performance of leather matrix towards eco-leather manufacture and effectively reduce emission of dyes from the source in leather manufacturing.

12.
Nano Lett ; 22(1): 263-270, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34905368

RESUMO

Nonuniform Li deposition causes dendrites and low Coulombic efficiency (CE), seriously hindering the practical applications of Li metal. Herein, we developed an artificial solid-state interphase (SEI) with planar polycyclic aromatic hydrocarbons (PAHs) on the surface of Li metal anodes by a facile in situ formation technology. The resultant dihydroxyviolanthron (DHV) layers serve as the protective layer to stabilize the SEI. In addition, the oxygen-containing functional groups in the soft and conformal SEI film can regulate the diffusion and transport of Li ions to homogenize the deposition of Li metal. The artificial SEI significantly improves the CEs and shows superior cyclability of over 1000 h at 4 mAh cm-2. The LiFePO4/Li cell (2.8 mAh cm-2) enables a long cyclability for 300 cycles and high CEs of 99.8%. This work offers a new strategy to inhibit Li dendrite growth and enlightens the design on stable SEI for metal anodes.

13.
J Neuroimmunol ; 362: 577787, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34923373

RESUMO

Myasthenia Gravis (MG) is a T cell-driven, autoantibody-mediated disease. Here we show that oral Berberine (BBR) ameliorated clinical symptoms of experimental autoimmune myasthenia gravis(EAMG) rat model via decreasing the frequencies of Th1, Th17, Th1/17 cell subsets. JAK-STAT pathway was highlighted by transcriptomic analysis with EAMG mononuclear cells (MNCs). Surface plasmon resonance identified ligand binding interaction between BBR and JAK2, and electrostatic interaction was proposed by molecular dynamic simulation. Reduced phosphorylated JAK1/2/3 and STAT1/3 in MNCs from BBR-fed EAMG rats were demonstrated. These results suggest that BBR might improve EAMG by rebalancing T cell subsets through targeting JAK-STAT pathway.

14.
J Sci Food Agric ; 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34854091

RESUMO

BACKGROUND: Food allergy has been regarded as a serious public nutritional health problem and attracted extensive attention all over the world, of which shellfish allergy is a long-lasting disorder that impacts health through a life-time. Sarcoplasmic calcium-binding protein (SCP) plays a vital role in cell and muscle functions and has been identified as an allergen in oyster. RESULTS: In this study, recombinant SCP (rSCP) with a molecular mass of 21 kDa was produced and identified based on SCP amino acid sequence of pacific oyster (Crassostrea gigas), and was used as a follow-up experimental material. Its physicochemical characterization showed that the purified rSCP is highly stable to heat, acid-alkali and trypsin digestion, but weaker to pepsin digestion. We established an animal sensitization model and rSCP displayed stronger IgE-binding activity with rats serum in the rSCP+ CT group compared with the CT group and control group. Most importantly, five epitope peptides were identified as linear immunodominant epitopes by indirect competitive enzyme-linked immunosorbent assay (icELISA) for the first time. In addition, we also found that conformational epitopes may play a major role in immunoreactivity of SCP. CONCLUSION: These results are significant for understanding hypersensitization of humans to oyster and offer available preventive measures and treatment programs in further research. This article is protected by copyright. All rights reserved.

15.
Adv Mater ; : e2106148, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34854504

RESUMO

Lithium-oxygen (Li-O2 ) batteries possess a high theoretical energy density, which means they could become a potential alternative to lithium-ion batteries. Nevertheless, the charging process of Li-O2 batteries requires much higher energy, due to the insulating nature of the discharge product. It has been revealed that the anion additive, lithium iodide (LiI), can tune the cell chemistry to form lithium hydroxide (LiOH) as the product and facilitate the kinetics during the charging process. Although numerous studies have been reported, the role of this additive is still under investigation. Herein, the recent advances focusing on the use of LiI in Li-O2 batteries are reviewed, its catalytic behavior on discharge and charge is discussed, and its synergistic effect with water is understood. The ambiguity existing among the studies are also revealed, and solutions to the current issues are introduced.

16.
Front Neurol ; 12: 679745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867700

RESUMO

Circular RNA (circNUP98) has been reported to promote renal cancer; however, its role in other cancers is unknown. The function of circNUP98 in glioblastoma (GB) cancer was explored in this study. A total of 58 GB tissue samples were collected to study the expression of circNUP98 and miR-519a-3p [both the mature and pre-mature microRNA (miRNA)] by quantitative real-time PCR (RT-qPCR) and heatmap analysis. The subcellular location that expresses circNUP98 was analyzed by nuclear fractionation assay. RNA pull-down assay was performed to evaluate the interaction between circNUP98 and pre-mature miR-519a-3p. Overexpression assays were performed to investigate the role of circNUP98 in the regulation of both the mature and pre-mature miR-519a-3p. The role of circNUP98 and miR-519a-3p in GB cell proliferation was explored by 5-bromo-2-deoxyuridine (BrdU) assay and was assessed in mouse xenograft model. Heatmap analysis showed that circNUP98 and pre-mature miR-519a-3p were upregulated in GB, while mature miR-519a-3p was downregulated in GB. Across the cancer tissues, circNUP98 was inversely correlated with mature miR-519a-3p, but positively correlated with pre-mature miR-519a-3p. In GB cells, circNUP98 was localized to both the nucleus and cytoplasm and it interacted with pre-mature miR-519a-3p. In GB cells, circNUP98 increased the expression levels of pre-mature miR-519a-3p and decreased the expression levels of mature miR-519a-3p. BrdU and cholecystokinin octapeptide (CCK-8) assays illustrated that overexpression of circNUP98 reduced the inhibitory effects of miR-519a-3p on cell proliferation. CircNUP98 contributed to larger tumors, which resulted in significantly reduced mice survival. CircNUP98 suppresses the maturation of miR-519a-3p to promote GB cell proliferation.

17.
Front Oncol ; 11: 745150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868942

RESUMO

Background: Diabetes mellitus (DM) is a frequent comorbidity in patients with cancer. This study aimed to evaluate the prognosis of advanced non-small cell lung cancer (NSCLC) patients with DM and to assess whether an optimal glycemic control improves overall survival (OS). Methods: A total of 1279 advanced NSCLC patients including 300 (23.5%) with preexisting DM were retrospectively reviewed. The continuous relationship between glycated hemoglobin A1C (HbA1c) level and OS was analyzed by restricted cubic spline (RCS) function. Optimal HbA1c cut-off point was determined using X-tile analysis. Survival was analyzed with the Kaplan-Meier method and compared among groups stratified by diabetes status and HbA1c. Multivariable Cox proportional hazards regression analysis was employed to identify prognostic factors for OS after adjusting for baseline characteristics. Results: DM and non-DM patients had similar OS (median (95% CI): 22.85 (20.05-26.73) vs. 22.22 (20.35-24.76) months, P=0.950). The multivariate Cox regression analyses showed that DM status was not a prognostic factor for OS (HR: 0.952, 95% CI: 0.808-1.122, P=0.559). However, there existed a non-linear but generally positive relationship between the elevated HbA1c level and increased risk of overall mortality. HbA1c > 6.6% was a negative prognostic factor for OS (HR: 1.593, 95% CI: 1.113-2.280, P=0.011). The median OS (95% CI) for nondiabetic patients, DM patients with HbA1c ≤6.6% and those with HbA1c > 6.6% was 22.22 (20.01-24.43), 25.28 (21.79-28.77) and 15.45 (7.57-23.33) months, respectively. Well-controlled DM patients had a comparable crude OS (HR (95% CI): 0.90 (0.76-1.08), P=0.273] compared to nondiabetic patients while patients with HbA1c>6.6% had a worse crude OS than patients without DM (HR (95% CI): 1.70 (1.24-2.34), P=0.001]. The survival benefit of good HbA1c control was prominent in all subgroups. Conclusion: Impaired glycemic level negatively affects survival for patients with advanced NSCLC while proper glycemic control with HbA1c ≤6.6% improves the OS.

18.
Front Pharmacol ; 12: 771588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880761

RESUMO

Acetylation is considered as one of the most common types of epigenetic modifications, and aberrant histone acetylation modifications are associated with the pathological process of cancer through the regulation of oncogenes and tumor suppressors. Recent studies have shown that immune system function and tumor immunity can also be affected by acetylation modifications. A comprehensive understanding of the role of acetylation function in cancer is essential, which may help to develop new therapies to improve the prognosis of cancer patients. In this review, we mainly discussed the functions of acetylase and deacetylase in tumor, immune system and tumor immunity, and listed the information of drugs targeting these enzymes in tumor immunotherapy.

19.
Front Oncol ; 11: 706409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858806

RESUMO

Objective: This retrospective study evaluated the survival advantage of local treatment targeted to brain metastases, relative to systemic therapy, as the first option for brain metastases of non-small cell lung cancer (NSCLC). Methods: First reviewed were 291 cases of NSCLC brain metastases from two centers. All patients were at least 18 years old, with histologically confirmed NSCLC, and required and underwent both local (radiotherapy or brain surgery) and systemic treatment (chemotherapy and tyrosine kinase inhibitor [TKI] medication). Demographics, clinical characteristics, and treatment-related variables were collected. Results: The final population comprised 160 patients. Overall, the multivariate analysis suggested that the following were associated with better survival: >3 cycles of chemotherapy; stereotactic radiosurgery; and TKI medication (all, P = 0.000). Local treatment that began within 1 week of the diagnosis of brain metastases was associated with poorer survival (P = 0.006). Among the 111 patients with symptomatic brain metastases, the multivariate analysis indicated that better survival was associated with >3 cycles of chemotherapy (P = 0.000), radiation dose >40 Gy (P = 0.001), stereotactic radiosurgery (P = 0.000), and TKI medication (P = 0.000), while local treatment that began within 1 week after the diagnosis of brain metastases was associated with poorer survival (P = 0.015). Conclusions: For patients with NSCLC brain metastases, regardless of the presence of clinical symptoms associated with brain metastases, systemic treatment before local may be better for survival. Even when used to relieve clinical symptoms, local treatment should be within a setting of sufficient systemic treatment.

20.
Front Oncol ; 11: 737323, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858817

RESUMO

Background: Modifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far. Methods: We developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX. Results: PPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4+ and CD8+ T cells was found in tumors from PPA1-DOX treated mice. Conclusions: We describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.

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