Publications by authors named "Ying Yuan"

688 Publications

Mobile Text Messaging for Tobacco Risk Communication Among Young Adult Community College Students: Randomized Trial of Project Debunk.

JMIR Mhealth Uhealth 2021 Nov 24;9(11):e25618. Epub 2021 Nov 24.

Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, United States.

Background: The use of new and emerging tobacco products (NETPs) and conventional tobacco products (CTPs) has been linked to several alarming medical conditions among young adults (YAs). Considering that 96% of YAs own mobile phones, SMS text messaging may be an effective strategy for tobacco risk communication.

Objective: Project Debunk is a community-based randomized trial aiming to identify specific types of messages that effectively improve perceived NETP and CTP risk among YAs in community colleges.

Methods: With YAs recruited offline from 3 campuses at the Houston Community College (September 2016 to July 2017), we conducted a 6-month randomized trial with 8 arms based on the combination of 3 message categories: framing (gain-framed vs loss-framed), depth (simple vs complex), and appeal (emotional vs rational). Participants received fully automated web-based SMS text messages in two 30-day campaigns (2 messages per day). We conducted repeated-measures mixed-effect models stratified by message type received, predicting perceived CTP and NETP risks. Owing to multiple testing with 7 models, an association was deemed significant for P<.007 (.05 divided by 7).

Results: A total of 636 participants completed the baseline survey, were randomized to 1 of 8 conditions (between 73 and 86 participants per condition), and received messages from both campaigns. By the 2-month post campaign 2 assessment point, 70.1% (446/636) completed all outcome measures. By the end of both campaigns, participants had a significant increase in perceived NETP risk over time (P<.001); however, participants had a marginal increase in perceived CTP risk (P=.008). Separately for each group, there was a significant increase in perceived NETP risk among participants who received rational messages (P=.005), those who received emotional messages (P=.006), those who received simple messages (P=.003), and those who received gain-framed messages (P=.003).

Conclusions: In this trial, YAs had an increase in perceived NETP risk. However, with stratification, we observed a significant increase in perceived NETP risk upon exposure to rational, emotional, simple, and gain-framed messages. In addition, YAs generally had an increase in perceived CTP risk and presented nonsignificant but observable improvement upon exposure to emotional, complex, and loss-framed messages. With the results of this study, researchers and practitioners implementing mobile health programs may take advantage of our tailored messages through larger technology-based programs such as smartphone apps and social media campaigns.

Trial Registration: ClinicalTrials.gov NCT03457480; https://clinicaltrials.gov/ct2/show/NCT03457480.

International Registered Report Identifier (irrid): RR2-10.2196/10977.
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http://dx.doi.org/10.2196/25618DOI Listing
November 2021

Lessons Learned From Implementing a Novel Bayesian Adaptive Dose-Finding Design in Advanced Pancreatic Cancer.

JCO Precis Oncol 2021 10;5. Epub 2021 Nov 10.

Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Novel Bayesian adaptive designs provide an effective way to improve clinical trial efficiency. These designs are superior to conventional methods, but implementing them can be challenging. The aim of this article was to describe what we learned while applying a novel Bayesian phase I-II design in a recent trial.

Methods: The primary goal of the trial was to optimize radiation therapy (RT) dose among three levels (low, standard, and high), given either with placebo (P) or an investigational agent (A), for treating locally advanced, radiation-naive pancreatic cancer, deemed appropriate for RT rather than surgery. Up to 48 patients were randomly assigned fairly between RT plus P and RT plus A, with RT dose-finding done within each arm using the late-onset efficacy-toxicity design on the basis of two coprimary end points, tumor response and dose-limiting toxicity, both evaluated at up to 90 days. The random assignment was blinded, but within each arm, unblinded RT doses were chosen adaptively using software developed within the institution.

Results: Implementing the design involved double-blind balance-restricted random assignment, real-time assessment of patient outcomes to evaluate the efficacy-toxicity trade-off for each RT dose in each arm to optimize each patient's RT dose adaptively, and transition from a single-center trial to a multicenter trial. We present lessons learned and illustrative documentation.

Conclusion: Implementing novel Bayesian adaptive trial designs requires close collaborations between physicians, pharmacists, statisticians, data managers, and sponsors. The process is difficult but manageable and essential for efficient trial conduct. Close collaboration during trial conduct is a key component of any trial that includes real-time adaptive decision rules.
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http://dx.doi.org/10.1200/PO.21.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594665PMC
November 2021

Hypothalamic subregion abnormalities are related to body mass index in patients with sporadic amyotrophic lateral sclerosis.

J Neurol 2021 Nov 15. Epub 2021 Nov 15.

Research Institute of Neuromuscular and Neurodegenerative Disease, Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, West Wenhua street No.107, Jinan, 250012, China.

Objective: To investigate atrophy patterns in hypothalamic subunits at different stages of ALS and examine correlations between hypothalamic subunit volume and clinical information.

Methods: We used the King's clinical staging system to divide 91 consecutive ALS patients into the different disease stages. We investigated patterns of hypothalamic atrophy using a recently published automated segmentation method in ALS patients and in 97 healthy controls. We recorded all subjects' demographic and clinical information.

Results: Compared with healthy controls, we found significant atrophy in the bilateral anterior-superior subunit and the superior tubular subunit, as well as a reduction in global hypothalamic volume in ALS patients. When we used the King's clinical staging system to divide patients into the different disease stages, we found neither global nor specific subunit atrophy until King's stage 3 in the hypothalamus. Moreover, specific subunit volumes were significantly associated with body mass index.

Conclusions: In a relatively large sample of Chinese patients with ALS, using a recently published automated segmentation method for the hypothalamus, we found the pattern of hypothalamic atrophy in ALS patients differed greatly across King's clinical disease stages. Moreover, specific hypothalamic subunit atrophy may play an important role in energy metabolism in ALS patients. Thus, our findings suggest that hypothalamic atrophy may have potential phenotypic associations, and improved energy metabolism may become an important component of individualised therapy for ALS.
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http://dx.doi.org/10.1007/s00415-021-10900-3DOI Listing
November 2021

BOIN: a novel Bayesian design platform to accelerate early phase brain tumor clinical trials.

Neurooncol Pract 2021 Dec 11;8(6):627-638. Epub 2021 Jun 11.

Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

Despite decades of extensive research, the progress in developing effective treatments for primary brain tumors lags behind that of other cancers, largely due to the unique challenges of brain tumors (eg, the blood-brain barrier and high heterogeneity) that limit the delivery and efficacy of many therapeutic agents. One way to address this issue is to employ novel trial designs to better optimize the treatment regimen (eg, dose and schedule) in early phase trials to improve the success rate of subsequent phase III trials. The objective of this article is to introduce Bayesian optimal interval (BOIN) designs as a novel platform to design various types of early phase brain tumor trials, including single-agent and combination regimen trials, trials with late-onset toxicities, and trials aiming to find the optimal biological dose (OBD) based on both toxicity and efficacy. Unlike many novel Bayesian adaptive designs, which are difficult to understand and complicated to implement by clinical investigators, the BOIN designs are self-explanatory and user friendly, yet yield more robust and powerful operating characteristics than conventional designs. We illustrate the BOIN designs using a phase I clinical trial of brain tumor and provide software (freely available at www.trialdesign.org) to facilitate the application of the BOIN design.
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http://dx.doi.org/10.1093/nop/npab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579094PMC
December 2021

Genome-wide selective detection of Mile red-bone goat using next-generation sequencing technology.

Ecol Evol 2021 Nov 12;11(21):14805-14812. Epub 2021 Oct 12.

Chongqing Key Laboratory of Forage & Herbivore College of Animal Science and Technology Chongqing Engineering Research Centre for Herbivores Resource Protection and Utilization Southwest University Chongqing China.

The ecotype population of goats () was created by long-term artificial selection and natural adaptation. Mile red-bone goat is an indigenous breed with visible red bones, and its special bone structure has received extensive attention. This study aimed to identify genetic variants and candidate genes associated with specific bone phenotypes using next-generation sequencing technology (NGS). The results revealed that 31,828,206 single nucleotide polymorphisms (SNPs) were obtained from 72 goats (20 Mile red-bone goats and 52 common goats) by NGS. A total of 100 candidate genes were identified on the basis top 1% window interaction from nucleotide diversity (), ratio ( / ), and pairwise fixation index ( ). Exactly 77 known signaling pathways were enriched. Specifically, three coding genes (, , and ) were annotated in the vitamin metabolism signaling pathways, and was annotated to the osteoclast (OC) differentiation pathway. Furthermore, 5862 reliable copy number variations (CNVs) were obtained, and 14 and 24 genes were annotated with the top 1‰ CNV based on (>0.490) and (>0.527), respectively. Several pathways related to bone development and metabolism of exogenous substances in vivo, including calcium signaling pathway, OC differentiation, and glycerophospholipid metabolism, were annotated. Specifically, six genes from 19 candidate CNVs, which were obtained by interaction of the top 1‰ CNVs with and , were annotated to mucin-type O-glycan biosynthesis and metabolic pathways. Briefly, the results implied that pseudopurpurin and specific genetic variants work together to contribute to the red-bone color and specific bone structure of Mile red-bone goat. This study is helpful to understanding the genetic basis of the unique bone phenotype of Mile red-bone goats.
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http://dx.doi.org/10.1002/ece3.8165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571596PMC
November 2021

Detection and analysis of common pathogenic germline mutations in Peutz-Jeghers syndrome.

World J Gastroenterol 2021 Oct;27(39):6631-6646

Department of Medical Oncology, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.

Background: Different types of pathogenic mutations may produce different clinical phenotypes, but a correlation between Peutz-Jeghers syndrome (PJS) genotype and clinical phenotype has not been found. Not all patients with PJS have detectable mutations of the gene, what is the genetic basis of clinical phenotypic heterogeneity of PJS? Do PJS cases without mutations have other pathogenic genes? Those are clinical problems that perplex doctors.

Aim: The aim was to investigate the specific gene mutation of PJS, and the correlation between the genotype and clinical phenotype of PJS.

Methods: A total of 24 patients with PJS admitted to the Air Force Medical Center, PLA (formerly the Air Force General Hospital, PLA) from November 1994 to January 2020 were randomly selected for inclusion in the study. One hundred thirty-nine common hereditary tumor-related genes including were screened and analyzed for pathogenic germline mutations by high-throughput next-generation sequencing (NGS). The mutation status of the genes and their relationship with clinical phenotypes of PJS were explored.

Results: Twenty of the 24 PJS patients in this group (83.3%) had gene mutations, 90% of which were pathogenic mutations, and ten had new mutation sites. Pathogenic mutations in exon 7 of gene were significantly lower than in other exons. Truncation mutations are more common in exons 1 and 4 of , and their pathogenicity was significantly higher than that of missense mutations. We also found gene mutations in PJS patients.

Conclusion: PJS has a relatively complicated genetic background. Changes in the sites responsible for coding functional proteins in exon 1 and exon 4 of may be one of the main causes of PJS. Mutation of the gene may be a cause of genetic heterogeneity in PJS.
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http://dx.doi.org/10.3748/wjg.v27.i39.6631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554407PMC
October 2021

An alcohol extract prepared from the male flower of Eucommia ulmoides Oliv. promotes synoviocyte apoptosis and ameliorates bone destruction in rheumatoid arthritis.

Chin Med 2021 Nov 6;16(1):113. Epub 2021 Nov 6.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong District, Shanghai, 201203, China.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease dominated by synovial hyperplasia and bone destruction. The male flower of Eucommia ulmoides Oliv. (EF) has been shown to exert effects on the inflammation caused by RA. However, how EF affects synoviocyte apoptosis and bone destruction on RA have not been investigated thoroughly. The effects of EF on apoptosis of human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) cells, osteoclast differentiation of RAW264.7 cells, and bone destruction in a collagen-induced arthritis (CIA) model in rats were explored.

Methods: First, the main components of EF were identified by high-performance liquid chromatography. In vitro, we investigated the anti-proliferative and pro-apoptotic effects of EF on HFLS-RA cells by immunofluorescence assays, flow cytometry, real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting; we also investigated how EF influenced the differentiation of RAW264.7 cells into osteoclasts. In vivo, we used a rat model of CIA to investigate the effects of EF on anti-arthritis activity, toe swelling, Arthritis Score, serum levels of metabolic bone factors, and pathologic conditions. Micro-computed tomography was used to scan ankle joints. mRNA and protein expression of factors related to the nuclear factor-kappa B (NF-κB) pathway were determined by RT-qPCR and western blotting, respectively.

Results: EF inhibited synoviocyte proliferation and promoted apoptosis in a dose-dependent manner. EF inhibited osteoclast differentiation by inhibiting activation of the NF-κB pathway. EF reduced articular inflammation in CIA rats, inhibited the expression of pro-angiogenic factors, and delayed the destruction of articular cartilage and bone. Our data indicated that EF acted via a mechanism related to bone metabolism induced by the NF-κB pathway.

Conclusions: EF exerts a potential therapeutic effect upon RA. Our research will help to elucidate the potential pharmacologic mechanisms associated with the beneficial effects of EF, and provide an experimental basis for EF application in clinical treatments.
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http://dx.doi.org/10.1186/s13020-021-00522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572500PMC
November 2021

Efficacy of the acupressure wrist-ankle strap in mild insomnia patients with anxiety disorders: study protocol for a randomized controlled trial.

Trials 2021 Nov 4;22(1):770. Epub 2021 Nov 4.

Department of Traditional Chinese Medicine, Naval Medical University, No. 800 Xiang Ying Road, Yangpu District, Shanghai, 200433, China.

Background: Insomnia is very common in current society, and patients are often accompanied by a certain degree of anxiety, depression, etc. Recent studies have found that the hypothalamic-pituitary-adrenal (HPA) axis excitement-inhibition state is an important indicator of sleep quality. Wrist-ankle acupuncture (WAA) is safe and effective for insomnia. Based on WAA theory, the acupressure wrist-ankle straps are portable WAA point compression straps that can treat diseases by automatically applying pressure to the treatment location and being operated by patients themselves. We design this trial to evaluate the clinical effect of the acupressure wrist-ankle strap in the treatment of mild insomnia patients with anxiety disorders.

Methods/design: This trial is a parallel-design, patients-assessor blinded, randomized, sham-controlled. In total, 114 patients diagnosed with mild insomnia and anxiety disorders will be randomly assigned into two groups, the acupressure wrist-ankle strap group or the non-acupressure wrist-ankle strap group; they will receive treatments for eight weeks with five sessions each week. Rating scales, sleep monitors, and laboratory tests will be used to observe the clinical effect. From the perspective of the circadian secretion of peripheral blood-related hormones in the hypothalamic-pituitary-adrenal (HPA) axis, the possible mechanism of acupressure wrist-ankle straps for treating insomnia is studied.

Discussion: The results of this study will confirm the efficacy of acupressure wrist-ankle strap in treating mild insomnia patients with anxiety disorder and whether its mechanism is related to the HPA axis. The acupressure wrist-ankle strap may become a pure physical, no side effect treatment of mild insomnia.

Trial Registration: Chinese Clinical Trial Registry ChiCTR2000039352 . Registered on 24 October 2020.
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http://dx.doi.org/10.1186/s13063-021-05725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567713PMC
November 2021

A Bayesian phase I/II platform design for co-developing drug combination therapies for multiple indications.

Stat Med 2021 Nov 3. Epub 2021 Nov 3.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

There is a growing trend to combine a new targeted or immunotherapy agent with the cancer-specific standard of care to treat different types of cancers. We propose a master-protocol-based, Bayesian phase I/II platform design to co-develop combination (BPCC) therapies in multiple indications. Under the BPCC design, only a single master protocol is needed, and the combined drug is evaluated in different indications in a concurrent or staggered fashion. For each indication, we jointly model dose-toxicity and -efficacy relationships and employ Bayesian hierarchical models to borrow information across them for more efficient indication-specific decision-making. To account for the characteristic of targeted or immunotherapy agents that their efficacy may not monotonically increase with the dose, and often plateau at high doses, we use the utility to quantify the risk-benefit tradeoff of the treatment. At each interim, we update the toxicity and efficacy model, as well as the estimate of the utility, based on the observed data across indications to inform the indication-specific decision of dose escalation and de-escalation and identify the optimal biological dose for each indication. Simulation study shows that the BPCC design has desirable operating characteristics, and that it provides an efficient approach to accelerate the development of combination therapies.
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http://dx.doi.org/10.1002/sim.9242DOI Listing
November 2021

Antineoplastic prescription among patients with colorectal cancer in eight major cities of China, 2015-2019: an observational retrospective database analysis.

BMJ Open 2021 10 27;11(10):e046166. Epub 2021 Oct 27.

Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Objectives: It is unclear what is driving rising colorectal cancer (CRC) treatment costs in China, whether an adjustment in drug prices changes use and total cost. This study aims to estimate trends in drug use, prescribing patterns and spending for antineoplastic drug therapies for CRC in major cities of China.

Methods: Information from 128 811 antineoplastic drug prescriptions in CRC was retrospectively collected from the Hospital Prescription Analysis Cooperative Project. The prescriptions extracted included demographic information of patients, the generic name and the price of antineoplastic drugs. The Mann-Kendall and Cochran-Armitage trend test was used to estimate the trends of antineoplastic agent usage.

Results: The number of antineoplastic prescriptions ranged from 18 966 in 2015 to 34 219 in 2019. Among the prescriptions collected in this study, the annual cost of antineoplastic drugs increased by 117.2%, and average prescription cost increased by 20%. Throughout the study period, the most prescribed antineoplastic drugs were capecitabine, oxaliplatin, fluorouracil and irinotecan, representing 49%, 27%, 21% and 9% of (per cent of visits (PV)). The PV of bevacizumab and cetuximab increased by 494% and 338% (from 1.8% and 1.3% in 2015 to 10.7% and 5.7% in 2019). In prescribing patterns of antineoplastic agents, monotherapy gradually decreased, while combination therapy, especially three-drug combination, increased significantly from 1.35% to 7.31%.

Conclusion: This study estimated recent trends of antineoplastic drug use and expenditure for Chinese patients with CRC. These results would inform CRC treatment decisions, including health insurance negotiation, precision therapy access, allocation of research funding and evaluation of the financial burden of CRC drug treatment.
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http://dx.doi.org/10.1136/bmjopen-2020-046166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552170PMC
October 2021

Effects of compost-derived humic acid on the bio-dechlorination of pentachlorophenol in high iron content paddy soil.

Ecotoxicol Environ Saf 2021 Dec 19;227:112900. Epub 2021 Oct 19.

State Environmental Protection Key Laboratory of Simulation and Control of Groundwater Pollution, Chinese Research Academy of Environmental Sciences, Beijing 100012, China. Electronic address:

Pentachlorophenol (PCP) is a common residual organic pollutant in paddy soil, and its harmful effects on soil ecosystems have been confirmed. Humic acid (HA) could act as an electron shuttle to promote the reductive dechlorination of PCP under anaerobic conditions. Humic-like substances produced by composting of kitchen waste were able to facilitate the reductive dechlorination of PCP during Fe(III) oxide reduction by iron-reducing bacteria. However, the effects of compost-derived HAs on reductive dechlorination of PCP in a paddy soil system with a high iron content have not been fully confirmed. The characteristics of HAs from different stages of composting during bio-dechlorination of PCP were still unclear. The functional components of compost-derived HAs, which are responsible for reductive dechlorination of PCP in different stages of composting, also need further investigation. In this study, we conducted a series of experiments on the Guangdong paddy soil system with high iron content (17.5 mg kg) to investigate the reductive dechlorination of PCP by HA in the early, middle, and later stages of food waste composting. The results showed that the middle- and late-stages of compost-derived HAs all promoted reductive dechlorination of PCP in the paddy system, but it was opposite in the early-stage. Significant differences were also presented in the components of HAs from different stages of composting. The early-stage compost-derived HAs contain numerous easy degradable components, it would inhibit the dechlorination of PCP by the changes of microbial metabolism in paddy soil. Compost-derived HAs in the middle composting stage showed the best reductive dechlorination effects on PCP. The reason might be that the compost-derived HAs in the middle composting stage could act both as electron donors and transfers. The electron transfer capacities (ETC) of middle-stage compost-derived HAs were significantly higher than those in the early and later composting stages. Compared with the natural HAs in the soil system, compost-derived HAs contained more chlorinated products with lower toxicities after the PCP degradation. This result mainly contributed to the detoxification and mineralization of PCP in the soil. These findings clarified the effects of compost-derived HAs on PCP bio-dechlorination in paddy soil with high iron content, identifying the optimal phase of compost-derived HA and providing a theoretical basis for the utilization of kitchen waste composting as a resource of HA.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112900DOI Listing
December 2021

Hippocampal subfield and anterior-posterior segment volumes in patients with sporadic amyotrophic lateral sclerosis.

Neuroimage Clin 2021 Sep 15;32:102816. Epub 2021 Sep 15.

Research Institute of Neuromuscular and Neurodegenerative Disease, Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China. Electronic address:

Neuroimaging studies of hippocampal volumes in patients with amyotrophic lateral sclerosis (ALS) have reported inconsistent results. Our aims were to demonstrate that such discrepancies are largely due to atrophy of different regions of the hippocampus that emerge in different disease stages of ALS and to explore the existence of co-pathology in ALS patients. We used the well-validated King's clinical staging system for ALS to classify patients into different disease stages. We investigated in vivo hippocampal atrophy patterns across subfields and anterior-posterior segments in different King's stages using structural MRI in 76 ALS patients and 94 health controls (HCs). The thalamus, corticostriatal tract and perforant path were used as structural controls to compare the sequence of alterations between these structures and the hippocampal subfields. Compared with HCs, ALS patients at King's stage 1 had lower volumes in the bilateral posterior subiculum and presubiculum; ALS patients at King's stage 2 exhibited lower volumes in the bilateral posterior subiculum, left anterior presubiculum and left global hippocampus; ALS patients at King's stage 3 showed significantly lower volumes in the bilateral posterior subiculum, dentate gyrus and global hippocampus. Thalamic atrophy emerged at King's stage 3. White matter tracts remained normal in a subset of ALS patients. Our study demonstrated that the pattern of hippocampal atrophy in ALS patients varies greatly across King's stages. Future studies in ALS patients that focus on the hippocampus may help to further clarify possible co-pathologies in ALS.
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http://dx.doi.org/10.1016/j.nicl.2021.102816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523912PMC
September 2021

Novel polymer-based system for intrauterine delivery of everolimus for anti-cancer applications.

J Control Release 2021 Nov 12;339:521-530. Epub 2021 Oct 12.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX 77030, United States of America. Electronic address:

Non-surgical treatment options for low-grade endometrial cancer and precancerous lesions are a critical unmet need for women who wish to preserve fertility or are unable to undergo hysterectomy. The PI3K/AKT/mTOR pathway is frequently activated in endometrial cancers and has been associated with resistance to endocrine therapy, making it a compelling target for early stage disease. Oral everolimus, an inhibitor against mTORC1, has shown clinical benefit in advanced or recurrent disease but has severe adverse effects that may lead to treatment interruption or dose reduction. To overcome this, we developed a polymer-based intrauterine delivery system to achieve persistent, local delivery of everolimus without systemic exposure. In vivo studies, using a rat model, showed that a poly(propylene fumarate)-based rod loaded with everolimus achieved everolimus delivery to the endometrium with levels similar to oral administration, but with limited systemic exposure and up to 84 days of release. Biological activity of everolimus delivered with this system was confirmed, measured by reduced lumen epithelial cell height and PI3K pathway biomarkers. This study shows a promising new delivery approach for anti-cancer drugs for non-surgical treatment of low-grade endometrial cancer.
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http://dx.doi.org/10.1016/j.jconrel.2021.10.008DOI Listing
November 2021

Histogram analysis of diffusion-weighted imaging and dynamic contrast-enhanced MRI for predicting occult lymph node metastasis in early-stage oral tongue squamous cell carcinoma.

Eur Radiol 2021 Oct 12. Epub 2021 Oct 12.

Department of Radiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200010, China.

Objectives: To investigate the feasibility of whole-tumor histogram analysis of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI for predicting occult lymph node metastasis (LNM) in early-stage oral tongue squamous cell cancer (OTSCC).

Materials And Methods: This retrospective study included 55 early-stage OTSCC (cT1-2N0M0) patients; 34 with pathological LNM and 21 without. Eight whole-tumor histogram features were extracted from quantitative apparent diffusion coefficient (ADC) maps and two semi-quantitative DCE parametric maps (wash-in and wash-out). The clinicopathological factors and histogram features were compared between the two groups. Stepwise logistic regression was used to identify independent predictors. Receiver operating characteristic curves were generated to assess the performances of significant variables and a combined model for predicting occult LNM.

Results: MRI-determined depth of invasion and ADC was significantly higher in the LNM group, with respective areas under the curve (AUCs) of 0.67 and 0.69, and accuracies of 0.73 and 0.73. ADC. ADC and wash-in were significantly lower in the LNM group, with respective AUCs of 0.68, 0.71, and 0.69, and accuracies of 0.65, 0.71, and 0.64. Histogram features from wash-out maps were not significantly associated with cervical node status. In the logistic regression analysis, ADC, ADC and wash-in were independent predictors. The combined model yielded the best predictive performance, with an AUC of 0.87 and an accuracy of 0.82.

Conclusions: Whole-tumor histogram analysis of ADC and wash-in maps is a feasible tool for preoperative evaluation of cervical node status in early-stage OTSCC.

Key Points: • Histogram analysis of parametric maps from DWI and DCE-MRI may assist the prediction of occult LNM in early-stage OTSCC. • ADC, ADC, and wash-in were independent predictors. • The combined model exhibited good predictive performance, with an accuracy of 0.82.
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http://dx.doi.org/10.1007/s00330-021-08310-0DOI Listing
October 2021

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study.

Lancet Haematol 2021 Nov 8;8(11):e818-e827. Epub 2021 Oct 8.

Weill Cornell Medicine, Meyer Cancer Center, New York, NY, USA.

Background: Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma.

Methods: We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m on day 1, intravenous etoposide 50 mg/m on days 1-4, oral prednisone 60 mg/m twice daily on days 1-5, intravenous vincristine 0·4 mg/m on days 1-4, intravenous cyclophosphamide 750 mg/m on day 5, and intravenous doxorubicin 10 mg/m on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed.

Findings: Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response.

Interpretation: Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448).

Funding: Genentech.
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http://dx.doi.org/10.1016/S2352-3026(21)00273-8DOI Listing
November 2021

Terahertz circular dichroism sensing of living cancer cells based on microstructure sensor.

Anal Chim Acta 2021 Oct 24;1180:338871. Epub 2021 Jul 24.

Institute of Modern Optics, Nankai University, Tianjin Key Laboratory of Micro-scale Optical Information Science and Technology, Tianjin, 300350, China; Tianjin Key Laboratory of Optoelectronic Sensor and Sensing Network Technology, Tianjin, 300350, China.

Terahertz (THz) waves have the advantages of being noninvasive and nonionizing because of their low radiation energy, so they have potential applications in the biomedical field, but thus far, those have been limited by the strong absorption in water and low detection sensitivity. Herein, we propose a reflective THz time-domain circular dichroism (CD) sensing system and a silicon subwavelength grating as the microstructure sensor to generate and detect the THz chiral polarization states, to realize quantitative detection of living cell numbers and qualitative identification of cell kinds in a liquid environment. Three kinds of hepatoma cell proliferation and inhibition with different concentrations of aspirin were measured by this sensing method, and the experimental results show that the sensitivities for CD resonance intensity and frequency shift can reach 3.44 dB mL/10 cells and 5.88 GHz mL/10 cells, respectively, and the minimum detection concentration is in the order of 10 cells/mL for THz detection in a liquid environment for the first time. This new THz sensing system and sensing method are expected to become a broadband, label-free, noncontact, real-time detection technology that can be used for quantitative detection and qualitative identification of cells or other active biochemical materials.
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http://dx.doi.org/10.1016/j.aca.2021.338871DOI Listing
October 2021

Nucleoporin 160 (NUP160) inhibition alleviates diabetic nephropathy by activating autophagy.

Bioengineered 2021 12;12(1):6390-6402

Department of Nephrology, Xinghua People's Hospital, Taizhou Jiangsu, China.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Autophagy was reported to be related to the pathogenesis of DN. This research investigated the function of the Nucleoporin 160 (Nup160) gene in regulating autophagy in DN. A mouse model of DN was established through an intraperitoneal injection of streptozotocin (STZ). Normal rat kidney tubular epithelial cells (NRK-52E) were treated with high glucose to induce DN in vitro. Real-time quantitative polymerase chain reaction (RT-qPCR), western blot, immunofluorescence assays were conducted to measure the expression of NUP160, autophagy-associated proteins, and inflammatory cytokines in vitro and in vivo. Pathological changes of kidney and liver tissues were analyzed using hematoxylin and eosin (H&E), Masson and periodic acid-silver (PAS) staining. The body weight, blood glucose, renal and lipid profiles of DN mice were examined. In this study, DN mice showed serious pathological injury. NUP160 expression was upregulated, autophagy was inhibited, and inflammatory response was increased in DN mice. Depletion of NUP160 restored autophagy and inhibited inflammation and fibrosis in high glucose (HG)-treated NRK-52E cells and STZ-induced DN mice by downregulating the expression of p62 and Collagen IV (Col-Ⅳ), increasing the ratio of LC3II/LC3I, and inactivating nuclear factor (NF)-κB signaling. Moreover, NUP160 knockdown could ameliorate pathological damage and glucose tolerance in DN mice. Overall, this study is the first to demonstrate the key role of NUP160 silencing in promoting autophagy against diabetic injury in DN.
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http://dx.doi.org/10.1080/21655979.2021.1968777DOI Listing
December 2021

HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats.

J Neuroinflammation 2021 Sep 16;18(1):205. Epub 2021 Sep 16.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, People's Republic of China.

Background: Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI.

Methods: A contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry.

Results: The protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes.

Conclusion: Collectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.
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http://dx.doi.org/10.1186/s12974-021-02271-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444373PMC
September 2021

Comparative proteome analysis of form-deprivation myopia in sclera with iTRAQ-based quantitative proteomics.

Mol Vis 2021 1;27:494-505. Epub 2021 Sep 1.

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai, China.

Objective: Scleral remodeling plays a key role in axial elongation in myopia. The aim of the present study was to identify the proteomics changes and specific signaling networks to gain insight into the molecular basis of scleral remodeling in myopic eyes.

Methods: Guinea pig form-deprivation myopia was induced with a translucent diffuser on a random eye for 4 weeks, while the other eye served as the contralateral control group. The axial length and refraction were measured at the beginning and end of the treatment. The proteins were extracted from the sclerae of each group and prepared for quantitative isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The coexpression networks and protein functions were analyzed using Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). Quantitative real-time PCR (qRT-PCR) and western blotting were performed to confirm the authenticity and accuracy of the iTRAQ results.

Results: After 4 weeks, the form-deprivation eyes developed significant degrees of myopia, and the axial length increased statistically significantly (p<0.05). A total of 2,579 unique proteins with <1% false discovery rate (FDR) were identified. Furthermore, 56 proteins were found to be upregulated, and 84 proteins were found to be downregulated, with a threshold of a 1.2-fold change and p<0.05 in the myopia group, when compared to the control group. Further bioinformatics analysis indicated that 44 of 140 differentially expressed proteins were involved in cellular movement and cellular assembly and organization. The qRT-PCR or western blotting results confirmed that myosin IIB, ACTIN3, and cellular cytoskeletons were downregulated, while RhoA and RAP1A were upregulated in the sclera in myopic eyes. These results were consistent with the proteomics results.

Conclusions: Proteomics and bioinformatics results can be helpful for identifying proteins and providing new insights for better understanding of the molecular mechanism underlying scleral remodeling. These results revealed that the proteins associated with cellular movement and cellular assembly and organization are altered during the development of myopia. Furthermore, RhoA plays a key role in the pathways involved in cellular movement and cellular assembly and organization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410231PMC
September 2021

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer.

Clin Cancer Res 2021 Sep 13. Epub 2021 Sep 13.

Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.

Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.

Experimental Design: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.

Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 ( = 6); therefore, DL1 was reexplored ( = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.

Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1656DOI Listing
September 2021

Elastic meta-analytic-predictive prior for dynamically borrowing information from historical data with application to biosimilar clinical trials.

Contemp Clin Trials 2021 11 17;110:106559. Epub 2021 Sep 17.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States. Electronic address:

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an approved reference product. Focusing on two-arm randomized clinical trials that aim to establish the equivalence between a test biosimilar product and the reference product, we propose the elastic meta-analytic-predictive (EMAP) prior method to leverage rich historical data available on the reference product to improve the power of the biosimilar trials. We first extract the prior information from multiple historical studies through meta-analysis, and then we discount the resulting meta-analytic-predictive (MAP) prior adaptively according to the congruence between the historical reference data and the trial reference arm data via an elastic function. The EMAP prior method is information-borrowing consistent in that asymptotically it achieves full information borrowing when trial reference arm data are congruent to historical reference data, and no information borrowing when trial reference arm data are not congruent to historical reference data. As a result, the method asymptotically controls the type I error rate at the nominal value. Extensive simulation studies show that the EMAP prior outperforms the robust MAP prior. The EMAP prior generates comparable or higher power and provides better-controlled type I errors. We illustrate the proposed methodology using two trial examples.
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http://dx.doi.org/10.1016/j.cct.2021.106559DOI Listing
November 2021

IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver.

Acta Pharmacol Sin 2021 Sep 8. Epub 2021 Sep 8.

Department of Cancer Research, Institute of Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.

The epigenetic modification of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a crucial role in cccDNA transcription and viral persistence. Interferon-α (IFN-α) is a pivotal agent against HBV cccDNA. However, the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood. In this study, we report that IFN-α2b enhances the histone deacetylase 3 (HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8 (H4K8) on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver. By screening acetyltransferases and deacetylases, we identified that HDAC3 was an effective restrictor of HBV transcription and replication. Moreover, we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells. Then, the 2-hydroxyisobutyrylation of histone H4K8 (H4K8hib) was identified on the HBV cccDNA minichromosome, promoting the HBV transcription and replication. The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system. The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice. The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients, which was consistent with the high transcriptional activity of cccDNA. Strikingly, IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells, leading to the inhibition of HBV transcription and replication. Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.
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http://dx.doi.org/10.1038/s41401-021-00765-7DOI Listing
September 2021

A comparison of three DFT exchange-correlation functionals and two basis sets for the prediction of the conformation distribution of hydrated polyglycine.

Authors:
Ying Yuan Feng Wang

J Chem Phys 2021 Sep;155(9):094104

Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, USA.

The performance of three density functional theory (DFT) exchange-correlation functionals, namely, Perdew-Burke-Ernzerhof (PBE), BP86, and B3LYP, in predicting conformational distributions of a hydrated glycine peptide is tested with two different basis sets in the framework of adaptive force matching (AFM). The conformational distributions yielded the free energy profiles of the DFT functional and basis set combinations. Unlike traditional validations of potential energy and structural parameters, our approach allows the free energy of DFT to be validated. When compared to experimental distributions, the def2-TZVP basis set provides better agreement than a slightly trimmed aug-cc-pVDZ basis set. B3LYP is shown to be better than BP86 and PBE. The glycine model fitted against B3LYP-D3(BJ) with the def2-TZVP basis set is the most accurate and named the AFM2021 model for glycine. The AFM2021 glycine model provides better agreement with experimental J-coupling constants than C36m and ff14SB, although the margin is very small when compared to C36m. Our previously published alanine model is also refitted with the slightly simplified AFM2021 energy expression. This work shows good promise of AFM for developing force fields for a range of proteinogenic peptides using only DFT as reference.
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http://dx.doi.org/10.1063/5.0059669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425985PMC
September 2021

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells.

J Hematol Oncol 2021 09 6;14(1):139. Epub 2021 Sep 6.

Department of Clinical Hematology, School of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.

Background: The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy.

Methods: Anti-BCR/ABL antibodies were encapsulated in poly(D, L-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles ([email protected] NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML.

Results: The results demonstrated that the [email protected] NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with [email protected] NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo.

Conclusions: In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.
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http://dx.doi.org/10.1186/s13045-021-01150-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422775PMC
September 2021

A new classification of congenital abnormalities of UPVS: sonographic appearances, screening strategy and clinical significance.

Insights Imaging 2021 Sep 6;12(1):125. Epub 2021 Sep 6.

Department of Ultrasound, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Hongli Road No. 2004, Futian, Shenzhen, 518028, Guangdong, China.

The umbilical-portal venous system (UPVS) plays an important role in embryonic development, as well as a significant blood circulation system to ensure the normal blood supply of fetal heart and brain and other vital organs. Congenital anomalies of UPVS contain many subtypes with a broad spectrum of manifestations and prognoses. Furthermore, because of fetal small lumen of UPVS, the sonographic evaluation remains difficult in utero. Appreciation of normal embryology and anatomy of UPVS is essential to an understanding of sonographic characteristics of anomalies of UPVS and fetal sequential changes. Through reviewing previous references and our experience with congenital abnormalities of UPVS, a new comprehensive classification is proposed. The new classification identifies three types of congenital abnormalities of UPVS based on morphological abnormalities and shunts. The embryology and etiology, sonographic, clinical and prognostic characteristics of each subtype of the new classification are described in detail. Knowledge of congenital abnormalities of UPVS can give sonographers a clue and aid prenatal sonographic diagnosis. The purpose of this article is to help the sonographers to understand the new classification of congenital abnormalities of UPVS, master the sonographic characteristics of each subtype and prenatal ultrasonographic screening strategy, and guide subsequent appropriate counseling and management.
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http://dx.doi.org/10.1186/s13244-021-01068-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421501PMC
September 2021

Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy.

Bioorg Med Chem 2021 Oct 10;47:116358. Epub 2021 Aug 10.

School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China. Electronic address:

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2021.116358DOI Listing
October 2021

Recent Advances and Challenges in Nanodelivery Systems for Antimicrobial Peptides (AMPs).

Antibiotics (Basel) 2021 Aug 16;10(8). Epub 2021 Aug 16.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.

Antimicrobial peptides (AMPs) can be used as alternative therapeutic agents to traditional antibiotics. These peptides have abundant natural template sources and can be isolated from animals, plants, and microorganisms. They are amphiphilic and mostly net positively charged, and they have a broad-spectrum inhibitory effect on bacteria, fungi, and viruses. AMPs possess significant rapid killing effects and do not interact with specific receptors on bacterial surfaces. As a result, drug resistance is rarely observed with treatments. AMPs, however, have some operational problems, such as a susceptibility to enzymatic (protease) degradation, toxicity in vivo, and unclear pharmacokinetics. However, nanodelivery systems loaded with AMPs provide a safe mechanism of packaging such peptides before they exert their antimicrobial actions, facilitate targeted delivery to the sites of infection, and control the release rate of peptides and reduce their toxic side effects. However, nanodelivery systems using AMPs are at an early stage of development and are still in the laboratory phase of development. There are also some challenges in incorporating AMPs into nanodelivery systems. Herein, an insight into the nanotechnology challenges in delivering AMPs, current advances, and remaining technological challenges are discussed in depth.
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http://dx.doi.org/10.3390/antibiotics10080990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388958PMC
August 2021

Elastic priors to dynamically borrow information from historical data in clinical trials.

Biometrics 2021 Aug 26. Epub 2021 Aug 26.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Use of historical data and real-world evidence holds great potential to improve the efficiency of clinical trials. One major challenge is to effectively borrow information from historical data while maintaining a reasonable type I error and minimal bias. We propose the elastic prior approach to address this challenge. Unlike existing approaches, this approach proactively controls the behavior of information borrowing and type I errors by incorporating a well-known concept of clinically significant difference through an elastic function, defined as a monotonic function of a congruence measure between historical data and trial data. The elastic function is constructed to satisfy a set of prespecified criteria such that the resulting prior will strongly borrow information when historical and trial data are congruent, but refrain from information borrowing when historical and trial data are incongruent. The elastic prior approach has a desirable property of being information borrowing consistent, that is, asymptotically controls type I error at the nominal value, no matter that historical data are congruent or not to the trial data. Our simulation study that evaluates the finite sample characteristic confirms that, compared to existing methods, the elastic prior has better type I error control and yields competitive or higher power. The proposed approach is applicable to binary, continuous, and survival endpoints.
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http://dx.doi.org/10.1111/biom.13551DOI Listing
August 2021

Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies.

J Clin Pharmacol 2021 Aug 25. Epub 2021 Aug 25.

Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.

Population pharmacokinetic (PK) and exposure-safety analyses of alisertib were performed in children enrolled in two clinical trials: NCT024448841 and NCT01154816.2 NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45-‍100 mg/m as powder-in-capsule once daily (QD) or twice daily (BID) for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours post-dose on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m as enteric-coated tablets QD for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours post-dose on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area (BSA) across the age range of 2-21 years, supporting the use of BSA-based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m QD enteric-coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg BID (recommended adult dose). Statistically significant relationships (p < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1958DOI Listing
August 2021

Subgroup Analysis by Liver Metastasis in the FRESCO Trial Comparing Fruquintinib versus Placebo Plus Best Supportive Care in Chinese Patients with Metastatic Colorectal Cancer.

Onco Targets Ther 2021 11;14:4439-4450. Epub 2021 Aug 11.

Eli Lilly and Company, Shanghai, People's Republic of China.

Objective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.

Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.

Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45-0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17-0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.

Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.

Clinicaltrialsgov Identifier: NCT02314819.
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http://dx.doi.org/10.2147/OTT.S307273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364970PMC
August 2021
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