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1.
J Nanobiotechnology ; 19(1): 126, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947395

RESUMO

BACKGROUND: Photothermal therapy (PTT), involving application of localized hyperthermia to kill cancer cells, has attracted wide attention in cancer therapy. The production of reactive oxygen species (ROS) during PTT may cause irreversible damage to healthy tissues around the tumor. Simultaneously, hyperthermia can stimulate inflammatory response, thus promoting tumor recurrence and metastasis. Therefore, it is of paramount importance to reduce the undesired side effects for further development of PTT. RESULTS: Using a hydrothermal method, spherical Prussian blue nanoparticles (PBs) with uniform size were prepared. The PBs exhibited good dispersion and stability in saline with an average hydrodynamic size of 110 nm. The prepared PBs had a high photothermal conversion efficiency and photothermal stability. The PBs showed intrinsic ROS scavenging properties in vitro. Antioxidant and anti-inflammatory effects of PBs were also observed in vivo. Assessment of toxicity and endoplasmic reticulum stress-inducing ability showed that PBs did not induce an inflammatory response. Tissues of major organs of mice stained with hematoxylin-eosin showed no significant damage, indicating good biocompatibility and safety of PBs. CONCLUSION: The designed single-component PBs with intrinsic ROS scavenging and anti-inflammatory properties could avoid inflammatory response and heat stress-induced ROS during PTT. Thus, further research on PBs is worthwhile to achieve their clinical translation and promote the development of PTT.

2.
Int J Food Sci Nutr ; : 1-12, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33870850

RESUMO

In vitro digestion of curdlan oligosaccharides (COSs), pullulan oligosaccharides (POSs), xanthan gum oligosaccharides (XGOSs) and gellan gum oligosaccharides (GGOSs) was investigated. These four oligosaccharides showed resistance to simulated saliva and gastric and small intestinal fluid. In further fermentation with faecal microbiota from healthy subjects and type 2 diabetes (T2D) patients, COS fermentation significantly increased the abundance of Bifidobacterium spp. and Lactobacillus spp. and the production of short-chain fatty acids in healthy and T2D groups. Digestion of XGOS enhanced the growth of the Clostridium leptum subgroup and significantly increased butyric acid production in healthy and T2D groups. Sole fermentation with COS, POS, XGOS and GGOS exhibited different metabolic profiles between healthy and T2D groups, and more small molecule polyols were produced in the T2D group than in the healthy group. This study provides a novel perspective on the reconstruction of gut microbiota and metabolism by POS, COS, GGOS and XGOS intervention.

3.
J Med Educ Curric Dev ; 8: 2382120520988597, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33786378

RESUMO

Objective: American College of Graduate Medical Education (ACGME) recommends ongoing care of 10 patients per resident however its implication is unclear. We hypothesized EMR quality to vary based on patient load and call status. Methods: We conducted a double-blind, single-center, retrospective observational study between 2017 and 2019 to investigate the quality and accuracy of resident documentation using the Responsible Electronic Documentation (RED) Checklist, a validated scoring system. Results: A total of 234 independent charts were analyzed and 80 met scoring criteria. Average patients per residents was 4, 9.1, 7.2, and 5.5 on "call" day (D0), "post-call" day (D1), "mid-call" day (D2), and "pre-call" day (D3), respectively. Mean RED checklist scores were 68.1%, 57%, 68.6%, and 72.1% on the above call status. The difference in score between D3 and D1 was statistically significant (P = .00042). There was a negative correlation between score and number of patients per resident (r = -0.286, P = .010). Conclusion: EMR documentation quality is directly impacted by patient load and resident call status with the lowest documentation quality on post-call day, correlating with patient load.

4.
Acta Biomater ; 126: 408-420, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33731303

RESUMO

The combination of chemotherapy and photothermal therapy (PTT) into a single formulation has attracted increasing attention as a strategy for enhancing cancer treatment. Here, hollow mesoporous silica nanoparticles (HMSNs) were used as a base carrier material, loaded with the anti-cancer drug doxorubicin (DOX), and surface functionalized with chitosan (CS) and copper sulfide (CuS) nanodots to give HMSNs-CS-DOX@CuS. In this formulation, the CuS dots act as gatekeepers to seal the surface pores of the HMSNs, preventing a burst release of DOX into the systemic circulation. S-S bonds connect the CuS dots to the HMSNs; these are selectively cleaved under the reducing microenvironment of the tumor, permitting targeted drug release. This, coupled with the PTT properties of CuS, results in a potent chemo/PTT platform. The HMSNs-CS-DOX@CuS nanoparticles have a uniform size (150 ± 13 nm), potent photothermal properties (η = 36.4 %), and tumor-targeted and near infrared (NIR) laser irradiation-triggered DOX release. In vitro and in vivo experimental results confirmed that the material has good biocompatibility, but is effectively taken up by cancer cells. Moreover, the CuS nanodots permit simultaneous thermal/photoacoustic dual-modality imaging. Treatment with HMSNs-CS-DOX@CuS and NIR irradiation caused extensive apoptosis in cancer cells both in vitro and in vivo, and could dramatically extend the lifetimes of animals in a murine breast cancer model. The system developed in this work therefore merits further investigation as a potential nanotheranostic platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Conventional cancer chemotherapy is accompanied by unavoidable off-target toxicity. Combination therapies, which can ameliorate these issues, are attracting significant attention. Here, the anticancer drug doxorubicin (DOX) was encapsulated in the central cavity of chitosan (CS)-modified hollow mesoporous silica nanoparticles (HMSNs). The prepared system can target drug release to the tumor microenvironment. When exposed to near infrared laser (NIR) irradiation, CuS nanodots located at the surface pores of the HMSNs generate energy, accelerating drug release. In addition, a systematic in vitro and in vivo evaluation confirmed the HMSNs-CS-DOX@CuS platform to give highly effective synergistic chemotherapeutic-photothermal therapy and have effective thermal/photoacoustic dual-imaging properties. This work may open up a new avenue for NIR-enhanced synergistic therapy with simultaneous thermal/photoacoustic dual imaging.

5.
Cancer Med ; 10(6): 2054-2062, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33619913

RESUMO

The state of Kentucky has the highest cancer incidence and mortality in the United States. High-risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate-high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high-TMB cohort compared to low-intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications which might help determine biomarkers that could benefit specific populations.

6.
PLoS One ; 16(1): e0244520, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33439872

RESUMO

Two new wood-inhabiting fungal species, Steccherinum tenuissimum and S. xanthum spp. nov. are described based on a combination of morphological features and molecular evidence. Steccherinum tenuissimum is characterized by an annual growth habit, resupinate basidiomata with an odontioid hymenial surface, a dimitic hyphal system with clamped generative hyphae, strongly encrusted cystidia and basidiospores measuring 3-5 × 2-3.5 µm. Steccherinum xanthum is characterized by odontioid basidiomata and a monomitic hyphal system with generative hyphae bearing clamp connections and covering by crystals, colourless, thin-walled, smooth, IKI-, CB-and has basidiospores measuring 2.7-5.5 × 1.8-4.0 µm. Sequences of the ITS and nLSU nrRNA gene regions of the studied samples were generated, and phylogenetic analyses were performed with maximum likelihood, maximum parsimony and Bayesian inference methods. The phylogenetic analyses based on molecular data of ITS + nLSU sequences showed that two new Steccherinum species felled into the residual polyporoid clade. Further investigation was obtained for more representative taxa in Steccherinum based on ITS + nLSU sequences, which demonstrated that S. tenuissimum and S. xanthum were sister to S. robustius with high support (100% BP, 100% BS and 1.00 BPP).


Assuntos
Filogenia , Polyporales/genética , China , DNA Fúngico/genética , Hifas/classificação , Hifas/genética , Hifas/crescimento & desenvolvimento , Polyporales/classificação , Polyporales/crescimento & desenvolvimento , Análise de Sequência de DNA , Esporos Fúngicos/classificação , Esporos Fúngicos/genética , Esporos Fúngicos/crescimento & desenvolvimento
7.
BMC Med ; 18(1): 406, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33349257

RESUMO

BACKGROUND: Colposcopy diagnosis and directed biopsy are the key components in cervical cancer screening programs. However, their performance is limited by the requirement for experienced colposcopists. This study aimed to develop and validate a Colposcopic Artificial Intelligence Auxiliary Diagnostic System (CAIADS) for grading colposcopic impressions and guiding biopsies. METHODS: Anonymized digital records of 19,435 patients were obtained from six hospitals across China. These records included colposcopic images, clinical information, and pathological results (gold standard). The data were randomly assigned (7:1:2) to a training and a tuning set for developing CAIADS and to a validation set for evaluating performance. RESULTS: The agreement between CAIADS-graded colposcopic impressions and pathology findings was higher than that of colposcopies interpreted by colposcopists (82.2% versus 65.9%, kappa 0.750 versus 0.516, p < 0.001). For detecting pathological high-grade squamous intraepithelial lesion or worse (HSIL+), CAIADS showed higher sensitivity than the use of colposcopies interpreted by colposcopists at either biopsy threshold (low-grade or worse 90.5%, 95% CI 88.9-91.4% versus 83.5%, 81.5-85.3%; high-grade or worse 71.9%, 69.5-74.2% versus 60.4%, 57.9-62.9%; all p < 0.001), whereas the specificities were similar (low-grade or worse 51.8%, 49.8-53.8% versus 52.0%, 50.0-54.1%; high-grade or worse 93.9%, 92.9-94.9% versus 94.9%, 93.9-95.7%; all p > 0.05). The CAIADS also demonstrated a superior ability in predicting biopsy sites, with a median mean-intersection-over-union (mIoU) of 0.758. CONCLUSIONS: The CAIADS has potential in assisting beginners and for improving the diagnostic quality of colposcopy and biopsy in the detection of cervical precancer/cancer.


Assuntos
Inteligência Artificial , Carcinoma de Células Escamosas/diagnóstico , Colposcopia/métodos , Detecção Precoce de Câncer/métodos , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Biópsia/métodos , Biópsia/estatística & dados numéricos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/prevenção & controle , China/epidemiologia , Colposcopia/estatística & dados numéricos , Confiabilidade dos Dados , Testes Diagnósticos de Rotina/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Valor Preditivo dos Testes , Gravidez , Reprodutibilidade dos Testes , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/prevenção & controle , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-33118610

RESUMO

INTRODUCTION: Osteoarthritis (OA) is a severe joint degeneration disease in elderly people described by the advanced degradation of articular cartilage, which ultimately leads to chronic pain. Trans-cinnamaldehyde (TCA) exerted its anti-inflammatory function in numerous disease syndromes; however, its role in the pathogenesis of OA remains unknown. The current research aimed to explore the potential protective impact of TCA in the progression of osteoarthritis in vitro. MATERIAL AND METHODS: Human knee articular chondrocytes were treated with 10 ng/ml IL-1ß alone for 24 h or in a combination in a pretreatment with TCA at different concentrations (2, 5, 10 µg/mL, 24 h). The viability and cell apoptosis were determined by CCK-8 assay and flow cytometry methods. The protein levels of IL-8, PGE2, and TNF-α and the levels of phosphorylated AKT and PI3K were evaluated using ELISA assay. Moreover, RT-qPCR was used to measure the relative mRNA expression of MMP-13, iNOS, COX-2, and ADAMTS-5 in IL-1ß-induced chondrocytes. RESULTS: Our results revealed that the treatment with TCA had no effect on chondrocytes' proliferation and apoptosis. Moreover, the protein levels of IL-8, TNF-α, and PGE2 were considerably reduced in IL-1ß-induced chondrocytes treated with different concentrations of TCA. Furthermore, the mRNA expression of MMP-13, iNOS, COX-2, and ADAMTS-5 and the phosphorylation of AKT and PI3K were markedly reduced in IL-1ß-induced chondrocytes with the increase in the concentration of TCA. CONCLUSIONS: Trans-cinnamaldehyde inhibited the inflammation induced by IL-1ß in chondrocytes through the PI3K/AKT pathway, which suggests that TCA might serve as a potential therapeutic agent for osteoarthritis treatment.

9.
Pharm Stat ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32869945

RESUMO

Cancer immunotherapy often reflects the improvement in both short-term risk reduction and long-term survival. In this scenario, a mixture cure model can be used for the trial design. However, the hazard functions based on the mixture cure model between two groups will ultimately crossover. Thus, the conventional assumption of proportional hazards may be violated and study design using standard log-rank test (LRT) could lose power if the main interest is to detect the improvement of long-term survival. In this paper, we propose a change sign weighted LRT for the trial design. We derived a sample size formula for the weighted LRT, which can be used for designing cancer immunotherapy trials to detect both short-term risk reduction and long-term survival. Simulation studies are conducted to compare the efficiency between the standard LRT and the change sign weighted LRT.

10.
IEEE J Biomed Health Inform ; 24(10): 2787-2797, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32816680

RESUMO

Coronavirus Disease 2019 (COVID-19) has rapidly spread worldwide since first reported. Timely diagnosis of COVID-19 is crucial both for disease control and patient care. Non-contrast thoracic computed tomography (CT) has been identified as an effective tool for the diagnosis, yet the disease outbreak has placed tremendous pressure on radiologists for reading the exams and may potentially lead to fatigue-related mis-diagnosis. Reliable automatic classification algorithms can be really helpful; however, they usually require a considerable number of COVID-19 cases for training, which is difficult to acquire in a timely manner. Meanwhile, how to effectively utilize the existing archive of non-COVID-19 data (the negative samples) in the presence of severe class imbalance is another challenge. In addition, the sudden disease outbreak necessitates fast algorithm development. In this work, we propose a novel approach for effective and efficient training of COVID-19 classification networks using a small number of COVID-19 CT exams and an archive of negative samples. Concretely, a novel self-supervised learning method is proposed to extract features from the COVID-19 and negative samples. Then, two kinds of soft-labels ('difficulty' and 'diversity') are generated for the negative samples by computing the earth mover's distances between the features of the negative and COVID-19 samples, from which data 'values' of the negative samples can be assessed. A pre-set number of negative samples are selected accordingly and fed to the neural network for training. Experimental results show that our approach can achieve superior performance using about half of the negative samples, substantially reducing model training time.


Assuntos
Betacoronavirus , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/diagnóstico , Interpretação de Imagem Radiográfica Assistida por Computador/estatística & dados numéricos , Aprendizado de Máquina Supervisionado , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Algoritmos , Estudos de Coortes , Biologia Computacional , Infecções por Coronavirus/classificação , Aprendizado Profundo , Erros de Diagnóstico/estatística & dados numéricos , Humanos , Redes Neurais de Computação , Pandemias/classificação , Pneumonia Viral/classificação , Estudos Retrospectivos
11.
Nanoscale ; 12(27): 14739-14750, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32626854

RESUMO

In this work, an innovative boron-based multifunctional nanoplatform was developed for synergistic chemotherapy/low temperature photothermal therapy (PTT). This platform is functionalized with a cRGD peptide to allow the targeting of αvß3 integrin, which is over-expressed in the cells of tumors. The nanoparticles were further loaded with the chemotherapeutic drug doxorubicin (DOX) and a heat shock protein inhibitor (17AAG), and high loading capacities for both DOX (603 mg g-1 B-PEG-cRGD) and 17AAG (417 mg g-1) were obtained. The resultant DOX-17AAG@B-PEG-cRGD system shows both pH-controlled and near-infrared (NIR)-induced DOX and 17AAG release. It also provides significantly enhanced cellular uptake in cancerous cells over healthy cells. The presence of 17AAG allows low-temperature PTT to be combined with chemotherapy with DOX, resulting in highly effective anti-cancer activity. This has been confirmed by both in vitro assays and using an in vivo murine cancer model. It is expected that such a multifunctional nanoplatform can serve as a promising candidate for cancer therapy.

12.
Oncotarget ; 11(16): 1427-1434, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32363000

RESUMO

BACKGROUND: We review factors impacting ipilimumab-associated adverse events through the experience from National Cancer Institute (NCI)-sponsored phase I immunotherapy clinical trials. MATERIALS AND METHODS: Attributable ipilimumab-related adverse events from NCI-sponsored phase I immunotherapy clinical trials were queried retrospectively by anonymized patient experience reports for observed adverse events like decreased hematological cell counts, blood electrolytes or proteins, or reduced patient performance status. The prevalence of ipilimumab-related toxicity was associated by patient to the duration of ipilimumab exposure, radiographic responses, progression-free survival, and overall survival. RESULTS: 373 patients from 11 phase 1 ipilimumab clinical trials were analyzed. Patients experiencing at least one grade 3 or 4 adverse event associated with observed radiographic response were included. The average number of grade 3/4 adverse events in responders was 1.167 versus 0.645 in non-responders (p = 0.001). Patient performance status did not significantly impact observed toxicity grade. Pretherapy lymphocyte count or chemistries were not associated with ipilimumab-associated toxicity. The number of agents combined with ipilimumab on trial was associated with average number of grade 3/4 toxicities-ipilimumab monotherapy (0.631) versus ipilimumab + 1 agent (0.877) versus ipilimumab + 2 agents (1.408) (p = 0.014). Number of low grade (grade 1/2) toxicities was associated with duration of treatment, Pearson correlation coefficient r = 0.456 (p < 0.0001); whereas the number of high grade (grade 3/4) toxicities was not, r = 0.032 (p = 0.546). CONCLUSIONS: Ipilimumab-attributed grade 3/4 toxicity was associated with therapeutic response. The number of co-administered agents added to ipilimumab significantly raised the likelihood of toxicity. Extended duration of treatment increased the incidence of low but not high-grade toxicity.

13.
Eur J Cancer ; 132: 35-42, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325418

RESUMO

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Prognóstico , Sorafenibe/administração & dosagem , Taxa de Sobrevida , Distribuição Tecidual , Adulto Jovem
14.
Diagnostics (Basel) ; 10(2)2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32098452

RESUMO

OBJECTIVE: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. METHODS: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. RESULTS: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3-1.25 µM) and ATRi (0.8-2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3-1.25 µM) and Chk1i(0.05-1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. CONCLUSIONS: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

15.
Nat Commun ; 11(1): 913, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060267

RESUMO

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.


Assuntos
Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/metabolismo , Proteína Nuclear Ligada ao X/genética , Animais , Pré-Escolar , Estudos de Coortes , Feminino , Amplificação de Genes , Humanos , Lactente , Masculino , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/genética , Espécies Reativas de Oxigênio/metabolismo , Proteína Nuclear Ligada ao X/metabolismo
16.
Appl Environ Microbiol ; 86(8)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033944

RESUMO

To enhance the growth performance of Saccharomyces cerevisiae under osmotic stress, mutant XCG001, which tolerates up to 1.5 M NaCl, was isolated through adaptive laboratory evolution (ALE). Comparisons of the transcriptome data of mutant XCG001 and the wild-type strain identified ELO2 as being associated with osmotic tolerance. In the ELO2 overexpression strain (XCG010), the contents of inositol phosphorylceramide (IPC; t18:0/26:0), mannosylinositol phosphorylceramide [MIPC; t18:0/22:0(2OH)], MIPC (d18:0/22:0), MIPC (d20:0/24:0), mannosyldiinositol phosphorylceramide [M(IP)2C; d20:0/26:0], M(IP)2C [t18:0/26:0(2OH)], and M(IP)2C [d20:0/26:0(2OH)] increased by 88.3 times, 167 times, 63.3 times, 23.9 times, 27.9 times, 114 times, and 208 times at 1.0 M NaCl, respectively, compared with the corresponding values of the control strain XCG002. As a result, the membrane integrity, cell growth, and cell survival rate of strain XCG010 increased by 24.4% ± 1.0%, 21.9% ± 1.5%, and 22.1% ± 1.1% at 1.0 M NaCl, respectively, compared with the corresponding values of the control strain XCG002 (wild-type strain with a control plasmid). These findings provided a novel strategy for engineering complex sphingolipids to enhance osmotic tolerance.IMPORTANCE This study demonstrated a novel strategy for the manipulation of membrane complex sphingolipids to enhance S. cerevisiae tolerance to osmotic stress. Elo2, a sphingolipid acyl chain elongase, was related to osmotic tolerance through transcriptome analysis of the wild-type strain and an osmosis-tolerant strain generated from ALE. Overexpression of ELO2 increased the content of complex sphingolipid with longer acyl chain; thus, membrane integrity and osmotic tolerance improved.


Assuntos
Osmose/fisiologia , Saccharomyces cerevisiae/fisiologia , Esfingolipídeos/biossíntese , Glicoesfingolipídeos/metabolismo , Osmorregulação
17.
Pharm Stat ; 19(4): 424-435, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32090453

RESUMO

The indirect mechanism of action of immunotherapy causes a delayed treatment effect, producing delayed separation of survival curves between the treatment groups, and violates the proportional hazards assumption. Therefore using the log-rank test in immunotherapy trial design could result in a severe loss efficiency. Although few statistical methods are available for immunotherapy trial design that incorporates a delayed treatment effect, recently, Ye and Yu proposed the use of a maximin efficiency robust test (MERT) for the trial design. The MERT is a weighted log-rank test that puts less weight on early events and full weight after the delayed period. However, the weight function of the MERT involves an unknown function that has to be estimated from historical data. Here, for simplicity, we propose the use of an approximated maximin test, the V0 test, which is the sum of the log-rank test for the full data set and the log-rank test for the data beyond the lag time point. The V0 test fully uses the trial data and is more efficient than the log-rank test when lag exits with relatively little efficiency loss when no lag exists. The sample size formula for the V0 test is derived. Simulations are conducted to compare the performance of the V0 test to the existing tests. A real trial is used to illustrate cancer immunotherapy trial design with delayed treatment effect.

18.
Theranostics ; 10(2): 841-855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903154

RESUMO

The hypoxia of the tumor microenvironment (TME) often hinders the effectiveness of cancer treatments, especially O2-dependent photodynamic therapy (PDT). Methods: An integrated iridium oxide (IrO2)-manganese dioxide (MnO2) nanotheranostic agent was fabricated through bovine serum albumin (BSA)-based biomineralization of Ir3+ and Mn2+. BSA was first covalently modified with chlorin e6 (Ce6), and used to fabricate multifunctional BSA-Ce6@IrO2/MnO2 nanoparticles (NPs) for computed X-ray tomography (CT) and photoacoustic (PA) imaging-guided PDT and photothermal (PTT) therapy of cancer. Extensive in vitro and in vivo studies were performed. Results: The theranostic agent produced can relieve tumor hypoxia by the decomposition of endogenous H2O2 in cancer cells to oxygen. The oxygen generated can be exploited for improved PDT. Paramagnetic Mn2+ released from the NPs in the acidic TME permits magnetic resonance imaging (MRI) to be performed. The exceptional photothermal conversion efficiency (65.3%) and high X-ray absorption coefficient of IrO2 further endow the NPs with the ability to be used in computed CT and PA imaging. Extensive antitumor studies demonstrated that the BSA-Ce6@IrO2/MnO2 nanoplatform inhibits cancer cell growth, particularly after combined PTT and PDT. Systematic in vivo biosafety evaluations confirmed the high biocompatibility of the nanoplatform. Conclusion: This work not only provides a novel strategy for designing albumin-based nanohybrids for theranostic applications but also provides a facile approach for extending the biomedical applications of iridium-based materials.

19.
Int J Radiat Oncol Biol Phys ; 107(1): 172-180, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987969

RESUMO

PURPOSE: Our purpose was to assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT). METHODS AND MATERIALS: Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this target volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n = 6), vincristine/dactinomycin/cyclophosphamide (n = 37), or vincristine/dactinomycin/cyclophosphamide-based combinations (n = 25). Patients were evaluated with primary-site magnetic resonance imaging, whole-body [18F]fluorodeoxyglucose positron emission tomography, and chest computed tomography for 5 years after treatment. RESULTS: Five-year disease-free survival was 88% for low-risk (n = 8), 76% for intermediate-risk (n = 37), and 36% for high-risk (n = 23) patients (P ≤ .01 for low risk/intermediate risk vs high risk). The cumulative incidence of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P < .01). Patients with head and neck primary tumors (n = 31) had a 35% cumulative incidence of cataracts; the risk correlated with lens dose (P = .0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P = .013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P = .041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9 of 14), bladder-wall thickening (10 of 14), and vaginal stenosis (2 of 5). CONCLUSIONS: Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach.


Assuntos
Radioterapia Conformacional/efeitos adversos , Rabdomiossarcoma/radioterapia , Segurança , Adolescente , Criança , Pré-Escolar , Ciclofosfamida/farmacologia , Intervalo Livre de Doença , Feminino , Fluordesoxiglucose F18 , Humanos , Lactente , Masculino , Margens de Excisão , Tomografia por Emissão de Pósitrons , Rabdomiossarcoma/diagnóstico por imagem , Fatores de Tempo , Adulto Jovem
20.
Adv Healthc Mater ; 9(2): e1901307, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31814332

RESUMO

A nanoplatform that integrates diagnostic and therapeutic functions with intrinsic tumor microenvironment-responsive biodegradability is highly desired. Herein, a biodegradable nanotheranostic agent based on hollow mesoporous organosilica nanoparticles (HMONs), followed by encapsulating of heat shock protein 90 (Hsp 90) inhibitor is described. Then, the pore-engineering including gating with bovine serum albumin-iridium oxide nanoparticles (BSA-IrO2 ) and conjugation of polyethylene glycol (PEG) is conducted to yield 17AAG@HMONs-BSA-IrO2 -PEG (AHBIP) nanotheranostics for multimode computed tomography (CT)/photoacoustic (PA) imaging-guided photodynamic therapy (PDT) and low-temperature photothermal therapy (PTT). Such nanoplatforms show extraordinary photothermal conversion efficiency, high cargo loading (35.4% for 17AAG), and stimuli-responsive release of 17AAG for inhibition of Hsp90, which induces cell apoptosis at low-temperatures (≈41 °C). Also, the IrO2 simultaneously endows the nanotheranostics with catalytic activity in triggering the decomposition of H2 O2 into O2 and thus reducing the tumor hypoxia, as well as protecting normal tissues against H2 O2 -induced inflammation. AHBIP shows good photocatalysis activity for PDT as a result of the generation of superoxide anion by laser irradiation. The resulting AHBIP-mediated synergistic PTT/PDT offers an outstanding therapeutic outcome both in vitro and in vivo. Overall, the incorporation of the BSA-IrO2 and biodegradable HMONs into one nanoplatform has great potential for clinical applications.

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