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1.
Small ; : e2402371, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38597692

RESUMO

Quantum dot (QD) light-emitting diodes (QLEDs) are promising for next-generation displays, but suffer from carrier imbalance arising from lower hole injection compared to electron injection. A defect engineering strategy is reported to tackle transport limitations in nickel oxide-based inorganic hole-injection layers (HILs) and find that hole injection is able to enhance in high-performance InP QLEDs using the newly designed material. Through optoelectronic simulations, how the electronic properties of NiOx affect hole injection efficiency into an InP QD layer, finding that efficient hole injection depends on lowering the hole injection barrier and enhancing the acceptor density of NiOx is explored. Li doping and oxygen enriching are identified as effective strategies to control intrinsic and extrinsic defects in NiOx, thereby increasing acceptor density, as evidenced by density functional theory calculations and experimental validation. With fine-tuned inorganic HIL, InP QLEDs exhibit a luminance of 45 200 cd m-2 and an external quantum efficiency of 19.9%, surpassing previous inorganic HIL-based QLEDs. This study provides a path to designing inorganic materials for more efficient and sustainable lighting and display technologies.

2.
Anticancer Res ; 44(2): 521-532, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38307549

RESUMO

BACKGROUND/AIM: The effectiveness of adoptive T cell therapy for solid tumors remains suboptimal, partly attributed to insufficient T cell infiltration into the tumor site. A promising strategy involves directing T cells towards the tumor utilizing tumor-specific chemokine receptors. MATERIALS AND METHODS: We analyzed chemokine receptor expression in activated T cells and chemokine expression in breast and lung cancer using The Cancer Genome Atlas (TCGA) data. Subsequently, we generated 1G4 T cell receptor-engineered T (TCR-T) cells with CCR10 and performed in vitro and in vivo efficacy tests. RESULTS: CCR10 exhibited insufficient expression in various human T cells. Analysis of TCGA RNA sequencing data revealed elevated expression of the chemokine CCL28, the corresponding chemokine for CCR10, in breast and lung cancer. Consequently, we generated CCR10-1G4 TCR-T cells. CCR10-1G4 dual expressing TCR-T cells exhibited comparable cellular cytotoxicity but increased mobility compared to 1G4 TCR-T cells in vitro. Furthermore, injecting CCR10-1G4 dual expressing TCR-T cells into a xenograft tumor model demonstrated enhanced in vivo trafficking and a greater reduction of tumor burden. CONCLUSION: This study highlights the potential of CCR10 for developing efficient adoptive T-cell treatments targeting solid tumors.


Assuntos
Neoplasias Pulmonares , Linfócitos T , Humanos , Linfócitos T/metabolismo , Quimiocinas/metabolismo , Receptores de Quimiocinas , Imunoterapia , Neoplasias Pulmonares/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores CCR10/genética , Receptores CCR10/metabolismo
3.
Pain Manag Nurs ; 25(2): e93-e98, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38135607

RESUMO

BACKGROUND: Post-operative pain is a common form of acute pain. Objective pain assessment in post-anesthesia care units after surgery is useful regardless of the patient's condition. AIMS: This study aimed to develop and evaluate an acute pain assessment tool for patients in post-anesthesia care units. DESIGN: This was a cross-sectional observational study comprising two stages: scale development and psychometric evaluation. SETTINGS:  . PARTICIPANTS/SUBJECTS:  . METHODS: Scale items were developed based on a literature review and content validity by experts. The validity and interrater reliability of the pain scale were evaluated using data from 218 patients admitted to the post-anesthesia care unit at a university hospital. A receiver operating characteristic curve was used to identify the sensitivity and specificity for determining the cutoff point for acute pain. RESULTS: We developed an objective acute pain scale, called the APA5, which ranges from 0-10 and comprises behavioral (facial and verbal expressions and body movement) and physiological (changes in heart rate and blood pressure) responses. The APA5 is valid and reliable for assessing acute pain in the recovery room. Sensitivity and specificity were acceptable when the cutoff was 2 out of 10 points. CONCLUSIONS: The APA5 is an easy and simple tool for measuring pain in patients in post-anesthesia care units who have difficulties with self-reporting.


Assuntos
Dor Aguda , Anestesia , Humanos , Dor Aguda/diagnóstico , Medição da Dor , Reprodutibilidade dos Testes , Estudos Transversais , Estudos Observacionais como Assunto
4.
Membranes (Basel) ; 13(8)2023 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-37623768

RESUMO

A cell filtration platform that affords accurate size separation and minimizes fouling was developed. The platform features an ultra-thin porous membrane (UTM) filter, a pumping head filtration with backflush (PHF), and cell size measurement (CSM) software. The UTM chip is an ultrathin free-standing membrane with a large window area of 0.68 mm2, a pore diameter of 5 to 9 µm, and a thickness of less than 0.9 µm. The PHF prevents filter fouling. The CSM software analyzes the size distributions of the supernatants and subnatants of isolated cells and presents the data visually. The D99 particle size of cells of the chronic myeloid leukemia (CML) line K562 decreased from 22.2 to 17.5 µm after passage through a 5-µm filter. K562 cells could be separated by careful selection of the pore size; the recovery rate attained 91.3%. The method was compared to conventional blocking models by evaluating the mean square errors (MSEs) between the measured and calculated filtering volumes. The filtering rate was fitted by a linear regression model with a significance that exceeded 0.99 based on the R2 value. The platform can be used to separate various soft biomaterials and afford excellent stability during filtration.

5.
Urol Oncol ; 41(10): 433.e19-433.e24, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37640571

RESUMO

BACKGROUND: There is limited ability to accurately diagnose and clinically stage patients with upper tract urothelial carcinoma (UTUC). The most easily available and widely used urinary biomarker is urine cytology, which evaluates cellular material yet lacks sensitivity. We sought to assess the feasibility of performing next-generation sequencing (NGS) on urine cytology specimens from patients with UTUC and evaluate the genomic concordance with tissue from primary tumor. METHODS: In this retrospective study, we identified 48 patients with a diagnosis of UTUC treated at Memorial Sloan Kettering Cancer Center (MSK) between 2019 and 2022 who had banked or fresh urine samples. A convenience cohort of matching, previously sequenced tumor tissue was used when available. Urine specimens were processed and the residual material, including precipitated cell-free DNA, was sequenced using our tumor-naïve, targeted exome sequencing platform that evaluates 505 cancer-related genes (MSK-IMPACT). The primary outcome was at least 1 detectable mutation in urinary cytology specimens. The secondary outcome was concordance to matched tissue (using ANOVA or Chi-Square, as indicated). RESULTS: Genomic sequencing was successful for 45 (94%) of the 48 urinary cytology patient samples. The most common mutations identified were TERT (62.2%), KMT2D (46.7%), and FGFR3 (35.6%). All patients with negative urine cytology and low-grade tissue had successful cytology sequencing. Thirty-six of the 45 patients had matching tumor tissue available; concordance to matched tissue was 55% overall (131 of the total 238 oncogenic or likely oncogenic somatic mutations identified). However, in 94.4% (n = 34/36) of patients, the cytology had at least 1 shared mutation with tissue. Eleven (30.6%) patients had 100% concordance between cytology and tissue. CONCLUSIONS: Sequencing urinary specimens from selective UTUC cytology is feasible in nearly all patients with UTUC. Prospective studies are underway to investigate a clinical role for this promising technology.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/patologia , Estudos Retrospectivos , Estudos Prospectivos , Estudos de Viabilidade , Genômica
6.
Clin Cancer Res ; 29(18): 3633-3640, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37406106

RESUMO

PURPOSE: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort. PATIENTS AND METHODS: The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance. RESULTS: 89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS. CONCLUSIONS: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation.


Assuntos
Neoplasias da Mama , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Feminino , Receptor ErbB-2/metabolismo , Receptor de Morte Celular Programada 1/uso terapêutico , Radioisótopos/uso terapêutico , Zircônio , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Trastuzumab/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
7.
Bioessays ; 45(7): e2200204, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37166068

RESUMO

Tumor-infiltrating lymphocyte (TIL) therapy is a promising approach for treating refractory or advanced solid cancers by using autologous TILs harvested from cancer tissues. Despite the heterogeneity of cancer, TIL therapy can potentially produce a positive therapeutic response, including complete remission. After decades of research on lymphocyte functions, culture/expansion methods, therapeutic protocols, and multiple clinical trials, TIL therapy has finally reached a stage where it can be formally approved for clinical use. TIL therapy is expected to hold a unique position among anti-cancer therapeutic options as a standard intervention. To successfully introduce TIL therapy into clinical settings, there is a need to expand therapeutic indications and set up the best protocols for cancer tissue sampling and manufacturing, and related clinical trials. Moreover, studies on next-generation TIL therapy have already begun, and post-approval real-world data will promote and support further research.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias , Humanos , Imunoterapia Adotiva/métodos , Neoplasias/terapia
8.
J Am Chem Soc ; 145(11): 6428-6433, 2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36897963

RESUMO

Indium phosphide (InP) quantum dots have enabled light-emitting diodes (LEDs) that are heavy-metal-free, narrow in emission linewidth, and physically flexible. However, ZnO/ZnMgO, the electron-transporting layer (ETL) in high-performance red InP/ZnSe/ZnS LEDs, suffers from high defect densities, quenches luminescence when deposited on InP, and induces performance degradation that arises due to trap migration from the ETL to the InP emitting layer. We posited that the formation of Zn2+ traps on the outer ZnS shell, combined with sulfur and oxygen vacancy migration between ZnO/ZnMgO and InP, may account for this issue. We synthesized therefore a bifunctional ETL (CNT2T, 3',3'″,3'″″-(1,3,5-triazine-2,4,6-triyl)tris(([1,1'-biphenyl]-3-carbonitrile)) designed to passivate Zn2+ traps locally and in situ and to prevent vacancy migration between layers: the backbone of the small molecule ETL contains a triazine electron-withdrawing unit to ensure sufficient electron mobility (6 × 10-4 cm2 V-1 s-1), and the star-shaped structure with multiple cyano groups provides effective passivation of the ZnS surface. We report as a result red InP LEDs having an EQE of 15% and a luminance of over 12,000 cd m-2; this represents a record among organic-ETL-based red InP LEDs.

9.
Front Immunol ; 14: 1070196, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36761730

RESUMO

Cell death and injury at the site of tumor ablation attracts macrophages. We sought to understand the status and activity of these cells while focusing on transforming growth factor-ß1 (TGF-ß1), a potent immunosuppressive and tumorigenic cytokine. Patients with urothelial cancer who underwent ablation using electrocautery or laser demonstrated increased infiltration and numbers of CD8+ T cells, along with FoxP3+ regulatory T cells, CD68+ macrophages and elevated levels of TGF-ß1 in recurrent tumors. Similar findings were reproduced in a mouse model of urothelial cancer (MB49) by partial tumor ablation with irreversible electroporation (IRE). Stimulation of bone marrow derived macrophages with MB49 cell debris produced using IRE elicited strong M2 polarization, with exuberant secretion of TGF-ß1. The motility, phenotypic markers and cytokine secretion by macrophages could be muted by treatment with Pirfenidone (PFD), a clinically approved drug targeting TGF-ß1 signaling. MB49 cancer cells exposed to TGF-ß1 exhibited increased migration, invasiveness and upregulation of epithelial-mesenchymal transition markers α-Smooth Muscle Actin and Vimentin. Such changes in MB49 cells were reduced by treatment with PFD even during stimulation with TGF-ß1. IRE alone yielded better local tumor control when compared with control or PFD alone, while also reducing the overall number of lung metastases. Adjuvant PFD treatment did not provide additional benefit under in vivo conditions.


Assuntos
Carcinoma de Células de Transição , Neoplasias Pulmonares , Neoplasias da Bexiga Urinária , Animais , Camundongos , Fator de Crescimento Transformador beta1/metabolismo , Macrófagos/metabolismo , Neoplasias Pulmonares/patologia , Transdução de Sinais , Neoplasias da Bexiga Urinária/metabolismo
10.
J Urol ; 209(5): 863-871, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36724067

RESUMO

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.


Assuntos
Carcinoma de Células de Transição , Fotoquimioterapia , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Fotoquimioterapia/métodos , Neoplasias Ureterais/patologia , Ureteroscopia/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico
11.
J Clin Oncol ; 41(8): 1618-1625, 2023 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-36603175

RESUMO

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Gencitabina , Cisplatino , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Terapia Neoadjuvante
13.
Nat Commun ; 13(1): 6575, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323682

RESUMO

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.


Assuntos
Carcinoma de Células Escamosas , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células de Transição/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Filogenia , Neoplasias da Bexiga Urinária/patologia , Linhagem da Célula
14.
Cancers (Basel) ; 14(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36358849

RESUMO

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease.

15.
Sci Rep ; 12(1): 17172, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229477

RESUMO

Submarine earthquakes have increased in the southwestern Ulleung Basin adjacent to the Korean Peninsula. This study analyzed the gravitational and magnetic properties of the three earthquake-prone areas (Hupo Bank and offshore regions near Pohang and Ulsan) in the basin. The basin was affected by tensile and compressive stresses during the formation of the East Sea. The southern Hupo Bank and the Pohang offshore exhibited high gravity anomalies and strong magnetic anomalies. Hupo Bank was separated from the peninsula and earthquakes in this region have been influenced by crustal fractures that facilitated igneous activities during the formation of the basin. Dense volcanic rocks and seaward dipping reflectors along the Pohang coast and continental slope suggest magmatic activities during the formation of the East Sea. Comparatively, the Ulsan offshore, with a thick sedimentary layer, exhibited a slightly higher gravity anomaly than the surrounding area, but no significant differences in the magnetic anomaly. Sequential tensile and compressive stresses related to the creation of the basin produced complex tectonic structures in this region. The magnetic tilt derivative results suggest that earthquakes were located near magnetic source boundaries. The results show that it is important to monitor earthquake-prone areas with gravity and magnetic anomalies.

16.
Nat Commun ; 12(1): 6397, 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34737304

RESUMO

A damaging Mw5.5 earthquake occurred at Pohang, South Korea, in 2017, after stimulating an enhanced geothermal system by borehole fluid injections. The earthquake was likely triggered by these operations. Current approaches for predicting maximum induced earthquake magnitude ([Formula: see text]) consider the volume of the injected fluid as the main controlling factor. However, these approaches are unsuccessful in predicting earthquakes, such as the Pohang one. Here we analyse the case histories of induced earthquakes, and find that [Formula: see text] scales with the logarithm of the elapsed time from the beginning of the fluid injection to the earthquake occurrence. This is also the case for the Pohang Earthquake. Its significant probability was predictable. These results validate an alternative to predicting [Formula: see text]. It is to monitor the exceedance probability of an assumed [Formula: see text] in real time by monitoring the seismogenic index, a quantity that characterizes the intensity of the fluid-induced seismicity per unit injected volume.

17.
Cancer Cell ; 39(9): 1245-1261.e6, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388376

RESUMO

The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Aurora Quinase B/antagonistas & inibidores , Proteína 11 Semelhante a Bcl-2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
18.
Molecules ; 26(12)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205347

RESUMO

PURPOSE: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. EXPERIMENTAL DESIGN: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. RESULTS: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. CONCLUSIONS: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.


Assuntos
Receptor de Morte Celular Programada 1/agonistas , Receptores OX40/agonistas , Neoplasias Urológicas/imunologia , Neoplasias Urológicas/terapia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade/efeitos dos fármacos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotoquimioterapia/métodos , Linfócitos T/efeitos dos fármacos , Neoplasias Urológicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Sci Rep ; 11(1): 4842, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649388

RESUMO

Locally advanced urothelial cancer has high recurrence and progression rates following surgical treatment. This highlights the need to develop neoadjuvant strategies that are both effective and well-tolerated. We hypothesized that neoadjuvant sub-ablative vascular-targeted photodynamic therapy (sbVTP), through its immunotherapeutic mechanism, would improve survival and reduce recurrence and progression in a murine model of urothelial cancer. After urothelial tumor implantation and 17 days before surgical resection, mice received neoadjuvant sbVTP (WST11; Tookad Soluble, Steba Biotech, France). Local and systemic response and survival served as measures of therapeutic efficacy, while immunohistochemistry and flow cytometry elucidated the immunotherapeutic mechanism. Data analysis included two-sided Kaplan-Meier, Mann-Whitney, and Fischer exact tests. Tumor volume was significantly smaller in sbVTP-treated animals than in controls (135 mm3 vs. 1222 mm3, P < 0.0001) on the day of surgery. Systemic progression was significantly lower in sbVTP-treated animals (l7% vs. 30%, P < 0.01). Both median progression-free survival and overall survival were significantly greater among animals that received sbVTP and surgery than among animals that received surgery alone (P < 0.05). Neoadjuvant-treated animals also demonstrated significantly lower local recurrence. Neoadjuvant sbVTP was associated with increased early antigen-presenting cells, and subsequent improvements in long-term memory and increases in effector and active T-cells in the spleen, lungs, and blood. In summary, neoadjuvant sbVTP delayed local and systemic progression, prolonged progression-free and overall survival, and reduced local recurrence, thereby demonstrating therapeutic efficacy through an immune-mediated response. These findings strongly support its evaluation in clinical trials.


Assuntos
Terapia Neoadjuvante , Neoplasias Experimentais/terapia , Fotoquimioterapia , Neoplasias da Bexiga Urinária/terapia , Animais , Masculino , Camundongos
20.
ACS Appl Mater Interfaces ; 13(9): 11396-11402, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33480686

RESUMO

Facile strategies in flexible transparent conductive electrode materials that can sustain their electrical conductivities under 1 mm-scale radius of curvature are required for wider applications such as foldable devices. We propose a rational design as well as a fabrication process for a silver nanowire-based transparent conductive electrode with low sheet resistance and high transmittance even after prolonged cyclic bending. The electrode is fabricated on a poly(ethylene terephthalate) film through the hybridization of silver nanowires with silver nanoparticles-anchored RuO2 nanosheets. This hybridization significantly improves the performance of the silver nanowire network under severe bending strain and creates an electrically percolative structure between silver nanowires and RuO2 nanosheets in the presence of anchored silver nanoparticles on the surface of RuO2 nanosheets. The resistance change of this hybrid transparent conductive electrode is 8.8% after 200,000 bending cycles at a curvature radius of 1 mm, making it feasible for use in foldable devices.

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