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1.
Cancer Immunol Immunother ; 73(1): 10, 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38231444

RESUMEN

The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.


Asunto(s)
Presentación de Antígeno , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteína p53 Supresora de Tumor/genética , Neoplasias de Cabeza y Cuello/genética , Cisplatino , Factor de Transcripción STAT1/genética , Péptidos y Proteínas de Señalización Intracelular
2.
BMC Public Health ; 24(1): 693, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38438990

RESUMEN

BACKGROUND: Second-hand smoking (SHS) increases the risk of chronic disease in adults and poses a serious health threat to children. Mass media campaigns are instrumental in raising awareness and reducing SHS exposure. There is a need to identify recent SHS mass media campaigns and assess their sustainability in terms of knowledge, attitudes, and behavioural changes. This systematic review summarises the characteristics and outcomes of mass media campaigns on SHS prevention. METHODS: PubMed, Embase, Web of Science, and grey literature were searched in November 2022 for SHS campaigns implemented between 2016 and 2022. The eligibility criteria included campaigns on the dangers or effects of SHS with any target group, dissemination medium, study design, or language. The database search identified 1,413 peer-reviewed titles, of which 82 full-texts were screened, with 14 meeting the eligibility criteria. The grey literature search identified 9,807 sources, of which 61 were included. We extracted data on the campaign characteristics, metrics, and smoking-related outcomes. The JBI critical appraisal tool was used to assess the risk of bias of the included studies. RESULTS: We found 73 SHS campaigns conducted between 2002 and 2022, across 50 countries. The campaigns reached 378 million people. The reported recall rates range from 8 to 76%. Of the 11 studies that reported smoking-related outcomes, 10 reported increased knowledge in understanding SHS risks (73-85%), five reported an increased prevalence of smoke-free homes, and two reported an increase in number of participants persuading others to quit smoking. Two studies reported a decrease in overall smoking, whereas three studies observed a reduction in smoking in the presence of children. CONCLUSION: The available data provide some support for the effectiveness of SHS campaigns in reducing smoking behaviours in homes and around children. However, the certainty of evidence was low due to the lack of a control group and the substantial heterogeneity in the outcomes assessed. Future campaigns need comprehensive evaluation and reporting to reduce publication bias.


Asunto(s)
Medios de Comunicación de Masas , Contaminación por Humo de Tabaco , Humanos , Fumar/epidemiología , Contaminación por Humo de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/prevención & control
3.
Zhongguo Zhong Yao Za Zhi ; 48(11): 2931-2939, 2023 Jun.
Artículo en Zh | MEDLINE | ID: mdl-37381953

RESUMEN

The U6 promoter is an important element driving sgRNA transcription in the CRISPR/Cas9 system. Seven PqU6 promo-ter sequences were cloned from the gDNA of Panax quinquefolium, and the transcriptional activation ability of the seven promoters was studied. In this study, seven PqU6 promoter sequences with a length of about 1 300 bp were cloned from the adventitious roots of P. quinquefolium cultivated for 5 weeks. Bioinformatics tools were used to analyze the sequence characteristics of PqU6 promoters, and the fusion expression vectors of GUS gene driven by PqU6-P were constructed. Tobacco leaves were transformed by Agrobacterium tumefaciens-mediated method for activity detection. The seven PqU6 promoters were truncated from the 5'-end to reach 283, 287, 279, 289, 295, 289, and 283 bp, respectively. The vectors for detection of promoter activity were constructed with GUS as a reported gene and used to transform P. quinquefolium callus and tobacco leaves. The results showed that seven PqU6 promoter sequences(PqU6-1P to PqU6-7P) were cloned from the gDNA of P. quinquefolium, with the length ranged from 1 246 bp to 1 308 bp. Sequence comparison results showed that the seven PqU6 promoter sequences and the AtU6-P promoter all had USE and TATA boxes, which are essential elements affecting the transcriptional activity of the U6 promoter. The results of GUS staining and enzyme activity test showed that all the seven PqU6 promoters had transcriptional activity. The PqU6-7P with a length of 1 269 bp had the highest transcriptional activity, 1.31 times that of the positive control P-35S. When the seven PqU6 promoters were truncated from the 5'-end(PqU6-1PA to PqU6-7PA), their transcriptional activities were different in tobacco leaves and P. quinquefolium callus. The transcriptional activity of PqU6-7PA promoter(283 bp) was 1.59 times that of AtU6-P promoter(292 bp) when the recipient material was P. quinquefolium callus. The findings provide more ideal endogenous U6 promoters for CRISPR/Cas9 technology in ginseng and other medicinal plants.


Asunto(s)
Panax , Panax/genética , Regiones Promotoras Genéticas , Agrobacterium tumefaciens/genética , Biología Computacional , Clonación Molecular
4.
J Asian Nat Prod Res ; 20(1): 92-100, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28675939

RESUMEN

A new homoisoflavanone, (3R)-5-hydroxy-7-methoxyl-3-(2'-hydroxy-4'- methoxybenzyl)-chroman-4-one (1), together with six known analogs, were isolated from the rhizomes of Polygonatum sibiricum. Their structures were elucidated on the basis of extensive spectroscopic analysis. All compounds were tested for their estrogenic activity using the MCF-7 estrogenresponsive human breast cancer cell lines. At a dose of 0.1 µmol/L, compounds 1-7 exhibited significant proliferative effects on MCF-7 cells compared with E2. The molecular docking study results indicated that the activity of compounds 3, 5, 6, and 7 may be the binding with ERR.


Asunto(s)
Medicamentos Herbarios Chinos/química , Estrógenos/aislamiento & purificación , Estrógenos/farmacología , Polygonatum/química , Rizoma/química , Estrógenos/química , Humanos , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Isoflavonas/farmacología , Células MCF-7 , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular
5.
Nanomedicine ; 12(7): 2031-2041, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27184097

RESUMEN

Carbohydrate receptors on alveolar macrophages are attractive targets for receptor-mediated delivery of nanostructured therapeutics. In this study, we employed reversible addition fragmentation chain transfer polymerization to synthesize neoglycopolymers, consisting of mannose- and galactose methacrylate-based monomers copolymerized with cholesterol methacrylate for use in functional liposome studies. Glycopolymer-functional liposomes were employed to elucidate macrophage mannose receptor (CD206) and macrophage galactose-type lectin (CD301) targeting in both primary macrophage and immortal macrophage cell lines. Expression of CD206 and CD301 was observed to vary significantly between cell lines (murine alveolar macrophage, murine bone marrow-derived macrophage, RAW264.7, and MH-S), which has significant implications in in vitro targeting and uptake studies. Synthetic glycopolymers and glycopolymer augmented liposomes demonstrated specific receptor-mediated uptake in a manner dependent on carbohydrate receptor expression. These results establish a platform capable of probing endogenous carbohydrate receptor-mediated targeting via glycofunctional nanomaterials.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Liposomas , Macrófagos Alveolares , Animales , Línea Celular , Portadores de Fármacos , Humanos , Lectinas , Macrófagos , Manosa , Ratones
6.
Proc Natl Acad Sci U S A ; 110(30): 12331-6, 2013 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-23836662

RESUMEN

The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.


Asunto(s)
Neoplasias de la Mama/metabolismo , Transición Epitelial-Mesenquimal , Regulación de la Expresión Génica/genética , Hipoxia/genética , Transportador 1 de Catión Orgánico/fisiología , Proteínas Circadianas Period/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Humanos , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Regulación hacia Arriba/genética
7.
Am J Pathol ; 182(3): 975-91, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23313138

RESUMEN

Prostate glands comprise two major epithelial cell types: luminal and basal. Luminal cells have long been considered the cellular origin of prostate cancer (CaP). However, recent evidence from a prostate regeneration assay suggests that prostate basal cells can also give rise to CaP. Here, we characterize Pten-deficient prostate lesions arising from keratin 5-expressing basal cells in a temporally controlled system in mice. Pten-deficient prostate lesions arising from basal cells exhibited luminal phenotypes with higher invasiveness, and the cell fate of Pten-deficient basal cells was traced to neoplastic luminal cells. After temporally ablating Pten in keratin 8-expressing luminal cells, luminal-derived Pten-deficient prostate tumors exhibited slower disease progression, compared with basal-derived tumors, within 13 weeks after Pten ablation. Cellular proliferation was significantly increased in basal-derived versus luminal-derived Pten-deficient prostate lesions. Increased tumor invasion into the smooth muscle layer and aberrantly regulated aggressive signatures (Smad4 and Spp1) were identified exclusively in basal-derived Pten-deficient lesions. Interestingly, p63-expressing cells, which represent basal stem and progenitor cells of basal-derived Pten-deficient prostate lesions, were significantly increased, relative to cells of the luminal-derived prostate lesion. Furthermore, castration did not suppress cellular proliferation of either basal-derived or luminal-derived Pten-deficient prostate tumors. Taken together, our data suggest that, although prostate malignancy can originate from both basal and luminal populations, these two populations differ in aggressive potential.


Asunto(s)
Diferenciación Celular , Eliminación de Gen , Fosfohidrolasa PTEN/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Andrógenos/deficiencia , Animales , Biomarcadores de Tumor/metabolismo , Castración , Diferenciación Celular/genética , Linaje de la Célula , Proliferación Celular , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Queratina-5 , Queratina-8/metabolismo , Masculino , Ratones , Ratones Transgénicos , Músculo Liso/patología , Invasividad Neoplásica , Fosfohidrolasa PTEN/deficiencia , Próstata/metabolismo , Neoplasias de la Próstata/cirugía , Regeneración , Proteínas Supresoras de Tumor/metabolismo
8.
RSC Adv ; 14(43): 31694-31703, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39376522

RESUMEN

This study introduces zwitterionic hyperbranched polymer (HBP) dots intercalated into layered double hydroxides (LDHs) for sustained antibacterial release. The proposed zwitterionic HBPs possess a three-dimensional spherical structure; unconventional blue fluorescent luminescence; water solubility; abundant COOH, amine, and amide functional groups; anionic exchangeability for intercalating into LDH interlayers; and sustained-release antibacterial activity. The intercalation for the layered nanomaterials was determined by adding different weight ratios of HBPs to Mg-Al LDHs to investigate the changes in the interlayer distance. X-ray diffraction revealed that the LDH layer spacing increased from 8.6 to 25.5 Å, effectively expanding the interlayer spacing with increasing HBP intercalation. Additionally, Fourier-transform infrared spectroscopy revealed the functional groups of the intercalated nanohybrids. Because the peripheral functional groups of HBPs are amino (-NH2) groups, preliminary evaluations revealed that pristine HBPs exhibited antibacterial properties. We further examined the antibacterial properties of the HBP/LDH nanohybrids. The results showed that HBPs combined with LDHs' controllable release properties can effectively achieve long-term sustained antibacterial release.

9.
Curr Opin Biotechnol ; 88: 103169, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38972172

RESUMEN

Immune cell therapies are an emerging class of living drugs that rely on the delivery of therapeutic transgenes to enhance, modulate, or restore cell function, such as those that encode for tumor-targeting receptors or replacement proteins. However, many cellular immunotherapies are autologous treatments that are limited by high manufacturing costs, typical vein-to-vein time of 3-4 weeks, and severe immune-related adverse effects. To address these issues, different classes of gene delivery vehicles are being developed to target specific immune cell subsets in vivo to address the limitations of ex vivo manufacturing, modulate therapeutic responses in situ, and reduce on- and off-target toxicity. The success of in vivo gene delivery to immune cells - which is being tested at the preclinical and clinical stages of development for the treatment of cancer, infectious diseases, and autoimmunity - is paramount for the democratization of cellular immunotherapies.


Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética , Humanos , Terapia Genética/métodos , Animales , Inmunoterapia/métodos
10.
J Stud Alcohol Drugs ; 2024 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-39480686

RESUMEN

BACKGROUND: The United States has seen a rapid increase in the use of Δ-8-tetrahydrocannabinol (Δ8-THC), a psychoactive compound similar to Δ-9-tetrahydrocannabinol (Δ9-THC). This study aimed to explore themes in Δ8-THC related tweets from U.S. jurisdictions with varying cannabis regulations from 2020 to 2022. METHODS: Tweets mentioning Δ8-THC were collected using search terms: D8, Delta-8, and Delta8 THC. The tweets were date-restricted from January 21, 2020, to May 31, 2022, resulting in 139,843 tweets. The final dataset included 61,800 U.S. tweets with complete location data. A subset of 1,000 tweets (n = 250 for each legal jurisdiction) was selected for content analysis. RESULTS: Three main themes related to Δ8-THC emerged across all jurisdictions: 'Sales and Advertising', 'Policy', and 'Personal Use'. In states where cannabis was legal for adult use, sales-themed tweets were most prevalent, promoting product sales and discounts. 'Policy' tweets were more common in medical CBD-only (34.5%) and fully illegal (24.8%) jurisdictions than in those with legalized medical (20.4%) and adult use (20.2%). Tweets about personal use appeared at similar rates in fully illegal (27.7%), medical (25.0%), medical CBD-only (24.5%), and fully legal jurisdictions (22.8%). Reports of adverse effects were frequent in tweets from fully illegal (28.9%), fully legal (27.7%), and medical (27.7%) jurisdictions, with the lowest frequency in medicinal CBD-only (15.6%) jurisdictions. CONCLUSION: The current study on the public discourse on Twitter indicates that discussions about the use and marketing of Δ8-THC are present in all U.S. jurisdictions, not just those without legal recreational cannabis markets.

11.
Clin Kidney J ; 17(1): sfad304, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38213491

RESUMEN

Background: Intradialytic hypotension (IDH) is a common hemodialysis complication causing adverse outcomes. Despite the well-documented associations of ambient temperatures with fluid removal and pre-dialysis blood pressure (BP), the relationship between ambient temperature and IDH has not been adequately studied. Methods: We conducted a cohort study at a tertiary hospital in southern Taiwan between 1 January 2016 and 31 October 2021. The 24-h pre-hemodialysis mean ambient temperature was determined using hourly readings from the weather station closest to each patient's residence. IDH was defined using Fall40 [systolic BP (SBP) drop of ≥40 mmHg] or Nadir90/100 (SBP <100 if pre-dialysis SBP was ≥160, or SBP <90 mmHg). Multivariate logistic regression with generalizing estimating equations and mediation analysis were utilized. Results: The study examined 110 400 hemodialysis sessions from 182 patients, finding an IDH prevalence of 11.8% and 10.4% as per the Fall40 and Nadir90/100 criteria, respectively. It revealed a reverse J-shaped relationship between ambient temperature and IDH, with a turning point around 27°C. For temperatures under 27°C, a 4°C drop significantly increased the odds ratio of IDH to 1.292 [95% confidence interval (CI) 1.228 to 1.358] and 1.207 (95% CI 1.149 to 1.268) under the Fall40 and Nadir90/100 definitions, respectively. Lower ambient temperatures correlated with higher ultrafiltration, accounting for about 23% of the increased IDH risk. Stratified seasonal analysis indicated that this relationship was consistent in spring, autumn and winter. Conclusion: Lower ambient temperature is significantly associated with an increased risk of IDH below the threshold of 27°C, irrespective of the IDH definition. This study provides further insight into environmental risk factors for IDH in patients undergoing hemodialysis.

12.
Nat Commun ; 14(1): 2102, 2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-37055393

RESUMEN

Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot reliably inform patient prognosis or genomic variations crucial for treatment selections. To address these challenges, we develop the Multi-omics Multi-cohort Assessment (MOMA) platform, an explainable machine learning approach, to systematically identify and interpret the relationship between patients' histologic patterns, multi-omics, and clinical profiles in three large patient cohorts (n = 1888). MOMA successfully predicts the overall survival, disease-free survival (log-rank test P-value<0.05), and copy number alterations of CRC patients. In addition, our approaches identify interpretable pathology patterns predictive of gene expression profiles, microsatellite instability status, and clinically actionable genetic alterations. We show that MOMA models are generalizable to multiple patient populations with different demographic compositions and pathology images collected from distinctive digitization methods. Our machine learning approaches provide clinically actionable predictions that could inform treatments for colorectal cancer patients.


Asunto(s)
Neoplasias Colorrectales , Multiómica , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Mutación , Inestabilidad de Microsatélites , Supervivencia sin Enfermedad
13.
Mol Pharm ; 9(5): 1271-9, 2012 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-22462641

RESUMEN

This study investigates the effects of chitosan (CS) on the opening of epithelial tight junctions (TJs) and paracellular transport at microscopic, ultrastructural, and computed-tomographic levels in Caco-2 cell monolayers and animal models. Using immunofluorescence staining, CS treatment was observed to be associated with the translocation of JAM-1 (a trans-membrane TJ protein), resulting in the disruption of TJs; the removal of CS was accompanied by the recovery of JAM-1. Ultrastructural observations by TEM reveal that CS treatment slightly opened the apical intercellular space, allowing lanthanum (an electron-dense tracer) to stain the intercellular surface immediately beneath the TJs, suggesting the opening of TJs. Following the removal of CS, the TJs were completely recovered. Similar microscopic and ultrastructural findings were obtained in animal studies. CS nanoparticles were prepared as an insulin carrier. The in vivo fluorescence-microscopic results demonstrate that insulin could be absorbed into the systemic circulation, while most CS was retained in the microvilli scaffolds. These observations were verified in a biodistribution study following the oral administration of isotope-labeled nanoparticles by single-photon emission computed tomography. Above results reveal that CS is a safe permeation enhancer and is an effective carrier for oral protein delivery.


Asunto(s)
Quitosano/química , Quitosano/metabolismo , Epitelio/metabolismo , Uniones Estrechas/metabolismo , Células CACO-2 , Moléculas de Adhesión Celular/metabolismo , Humanos , Microscopía Electrónica de Transmisión , Nanopartículas/química , Nanopartículas/ultraestructura , Receptores de Superficie Celular/metabolismo , Uniones Estrechas/ultraestructura
14.
Nat Biomed Eng ; 6(3): 310-324, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35241815

RESUMEN

Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered protease activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. The sensors consist of a library of mass-barcoded protease substrates that, when cleaved by tumour proteases and immune proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random forest classifiers trained on mass spectrometry signatures from a library of αPD1-conjugated mass-barcoded activity sensors for differentially expressed tumour proteases and immune proteases can be used to detect early antitumour responses and discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Biomarkers of protease activity may facilitate the assessment of early responses to ICB therapy and the classification of refractory tumours based on resistance mechanisms.


Asunto(s)
Inmunoconjugados , Neoplasias , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Péptido Hidrolasas , Urinálisis
15.
Sci Adv ; 8(8): eabm7950, 2022 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-35196075

RESUMEN

Simultaneous delivery of mRNA to multiple populations of antigen (Ag)-specific CD8+ T cells is challenging given the diversity of peptide epitopes and polymorphism of class I major histocompatibility complexes (MHCI). We developed Ag-presenting nanoparticles (APNs) for mRNA delivery using pMHCI molecules that were refolded with photocleavable peptides to allow rapid ligand exchange by UV light and site-specifically conjugated with a lipid tail for postinsertion into preformed mRNA lipid nanoparticles. Across different TCR transgenic mouse models (P14, OT-1, and Pmel), UV-exchanged APNs bound and transfected their cognate Ag-specific CD8+ T cells equivalent to APNs produced using conventionally refolded pMHCI molecules. In mice infected with PR8 influenza, multiplexed delivery of UV-exchanged APNs against three immunodominant epitopes led to ~50% transfection of a VHH mRNA reporter in cognate Ag-specific CD8+ T cells. Our data show that UV-mediated peptide exchange can be used to rapidly produce APNs for mRNA delivery to multiple populations of Ag-specific T cells in vivo.

16.
Adv Healthc Mater ; 10(15): e2100157, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33887123

RESUMEN

The clinical success of cancer immunotherapy is providing exciting opportunities for the development of new methods to detect and treat cancer more effectively. A new generation of biomaterials is being developed to interface with molecular and cellular features of immunity and ultimately shape or control anti-tumor responses. Recent advances that are supporting the advancement of engineered T cells are focused here. This class of cancer therapy has the potential to cure disease in subsets of patients, yet there remain challenges such as the need to improve response rates and safety while lowering costs to expand their use. To provide a focused overview, recent strategies in three areas of biomaterials research are highlighted: low-cost cell manufacturing to broaden patient access, noninvasive diagnostics for predictive monitoring of immune responses, and strategies for in vivo control that enhance anti-tumor immunity. These research efforts shed light on some of the challenges associated with T cell immunotherapy and how engineered biomaterials that interface with synthetic immunity are gaining traction to solve these challenges.


Asunto(s)
Materiales Biocompatibles , Neoplasias , Humanos , Factores Inmunológicos , Inmunoterapia , Neoplasias/terapia , Linfocitos T
17.
Adv Ther (Weinh) ; 4(8)2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34541300

RESUMEN

Adoptive T cell therapies are transforming the treatment of solid and liquid tumors, yet their widespread adoption is limited in part by the challenge of generating functional cells. T cell activation and expansion using conventional antigen-presenting cells (APCs) is unreliable due to the variable quality of donor-derived APCs. As a result, engineered approaches using nanomaterials presenting T cell activation signals are a promising alternative due to their ability to be robustly manufactured with precise control over stimulation cues. In this work, we design synthetic APCs that consist of liposomes surface-functionalized with peptide-major histocompatibility complexes (pMHC). Synthetic APCs selectively target and activate antigen-specific T cell populations to levels similar to conventional protocols using non-specific αCD3 and αCD28 antibodies without the need for costimulation signals. T cells treated with synthetic APCs produce effector cytokines and demonstrate cytotoxic activity when co-cultured with tumor cells presenting target antigen in vitro. Following adoptive transfer into tumor-bearing mice, activated cells control tumor growth and improve overall survival compared to untreated mice. Synthetic APCs could potentially be used in the future to improve the accessibility of adoptive T cell therapies by removing the need for conventional APCs during manufacturing.

18.
J Control Release ; 330: 284-292, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33221351

RESUMEN

Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen's intrinsic antibiotic resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in under-resourced settings. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with an aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's relative resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.


Asunto(s)
Melioidosis , Profármacos , Animales , Humanos , Pulmón , Macrófagos Alveolares , Melioidosis/tratamiento farmacológico , Melioidosis/prevención & control , Ratones , Polímeros
19.
Free Radic Biol Med ; 165: 368-384, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33460768

RESUMEN

Emerging evidences implicate the contribution of ROS to T cell activation and signaling. The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we show that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, results in T cell hyperproliferation and elevated cytokine productions. T cell-specific NPGPx-knockout mice reveal enhanced T-dependent humoral responses and are susceptible to experimental autoimmune encephalomyelitis (EAE). Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. NPGPx is activated by ROS generated from TCR stimulation, and modulates ZAP70 activity through redox switching to reduce ZAP70 recruitment to TCR/CD3 complex in membrane lipid raft, therefore subduing TCR responses. These results reveal a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis.


Asunto(s)
Proteómica , Linfocitos T , Animales , Homeostasis , Ratones , Oxidación-Reducción , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/metabolismo
20.
Yao Xue Xue Bao ; 45(6): 742-6, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20939183

RESUMEN

To study the chemical constituents of Saxifraga stolonifera (L.) Meeb., chromatographic techniques were applied to separate and purify the compounds, and their structures were confirmed on the basis of physicochemical properties and spectral data. Ten compounds were isolated and identified as 5-O-methylnorbergenin (1), 3, 4-dihydroxyallylbenzene-4-O-beta-D-glucopyranoside (2), (7R, 8S)-4, 9, 9'-trihydroxyl-3-methoxyl-7, 8-dihydrobenzofuran-1'-propylneolignan-3'-O-beta-D-glucopyranoside (3), quercetin-3-O-beta-D-xylopyranosyl-(1 --> 2)-beta-D-galactopyranoside (4), kaempferol-3-O-alpha-L-rhamnopyranoside (5), (3S, 5R, 6R, 7E, 9R)-3, 5, 6, 9-tetrahydroxy-7-megastigmane (6), benzyl-O-alpha-L-rhamnopyranosyl-(1 --> 6)-beta-D-glucopyranoside (7), p-hydroxyacetophenone (8), pyrogallic acid (9) and p-hydroxyphenol (10). Compound 1 is a new compound. Compounds 2-10 were isolated from this plant for the first time.


Asunto(s)
Benzopiranos/química , Benzopiranos/aislamiento & purificación , Plantas Medicinales/química , Saxifragaceae/química , Acetofenonas/química , Acetofenonas/aislamiento & purificación , Benzofuranos/química , Benzofuranos/aislamiento & purificación , Glicósidos/química , Glicósidos/aislamiento & purificación , Estructura Molecular , Pirogalol/química , Pirogalol/aislamiento & purificación
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