Publications by authors named "Zhaohui Jin"

72 Publications

Research on Anal Squamous Cell Carcinoma: Systemic Therapy Strategies for Anal Cancer.

Cancers (Basel) 2021 May 1;13(9). Epub 2021 May 1.

Department of Medical Oncology, Mayo Clinic, Rochester, MN 55903, USA.

Anal squamous cell carcinoma (ASCC) is a rare malignancy, with most cases associated with human papilloma virus and an increased incidence in immunocompromised patients. Progress in management of ASCC has been limited not only due to its rarity, but also the associated lack of research funding and social stigma. Historically, standard of care for invasive ASCC has been highly morbid surgical resection, requiring a permanent colostomy. Surgery was associated with disease recurrence in approximately half of the patients. However, the use of chemotherapy (5-fluorouracil and mitomycin C) concomitantly with radiation in the 1970s resulted in disease regression, curing a subset of patients and sparing them from morbid surgery. Validation of the use of systemic therapy in prospective trials was not achieved until approximately 20 years later. In this review, advancements and shortcomings in the use of systemic therapy in the management of ASCC will be discussed. Not only will standard-of-care systemic therapies for locoregional and metastatic disease be reviewed, but the evolving role of novel treatment strategies such as immune checkpoint inhibitors, HPV-based vaccines, and molecularly targeted therapies will also be covered. While advances in ASCC treatment have remained largely incremental, with increased biological insight, an increasing number of promising systemic treatment modalities are being explored.
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http://dx.doi.org/10.3390/cancers13092180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125190PMC
May 2021

Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.

J Natl Cancer Inst 2021 Jun 1. Epub 2021 Jun 1.

Department of Gastrointestinal Onocology, Keck School of Medicine at USC, Los Angeles, CA, USA.

Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.

Methods: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided.

Results: Compared to right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness.

Conclusions: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
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http://dx.doi.org/10.1093/jnci/djab112DOI Listing
June 2021

The influence of negative emotional intensity on dual-processing recognition.

Biol Psychol 2021 04 24;161:108083. Epub 2021 Mar 24.

Key Laboratory of Jiangxi Province for Psychology and Cognition Science, School of Psychology, Jiangxi Normal University, Nanchang, 330022, China. Electronic address:

Dual-processing theory assumes recognition memory involves two distinct processes: familiarity and recollection. Although the influence of emotional intensity on memory has been investigated, it remains unclear whether the influence of negative stimuli depends on familiarity or recollection. This study recorded event-related potentials as participants performed a modified remember/know procedure with highly negative, mildly negative, and neutral stimuli. The results showed that, relative to highly negative stimuli, mildly negative and neutral stimuli showed increased mean discrimination for responses of 'know' in the following pattern: highly negative < mildly negative < neutral. Neutral stimuli enhanced the frontal old/new effect. Relative to mildly negative and neutral stimuli, highly negative stimuli showed increased mean discrimination for responses of 'remember', and enhanced the parietal old/new effect. These results suggested negative emotional intensity influences recollection and familiarity differently, as recognition of highly negative stimuli depends on recollection, and recognition of neutral stimuli depends on familiarity.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108083DOI Listing
April 2021

Neuroprotection of Chikusetsu saponin V on transient focal cerebral ischemia/reperfusion and the underlying mechanism.

Phytomedicine 2021 Apr 17;84:153516. Epub 2021 Feb 17.

Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Background: Oxidative stress and frequently unwanted alterations in mitochondrial structure and function are key aspects of the pathological cascade in transient focal cerebral ischemia. Chikusetsu saponin V (CHS V), a major component of saponins from Panax japonicas, can attenuate HO-induced oxidative stress in SH-SY5Y cells.

Purpose: The aim of the present study was to investigate the neuroprotective effects and the possible underlying mechanism of CHS V on transient focal cerebral ischemia/reperfusion.

Methods: Mice with middle cerebral artery occlusion (MCAO) and cultured cortical neurons exposed to oxygen glucose deprivation (OGD) were used as in vivo and in vitro models of cerebral ischemia, respectively. The neurobehavioral scores, infarction volumes, H&E staining and some antioxidant levels in the brain were evaluated. The occurrence of neuronal death was estimated. Total and mitochondrial reactive oxygen species (ROS) levels, as well as mitochondrial potential were measured using flow cytometry analysis. Mitochondrial structure and respiratory activity were also examined. Protein levels were investigated by western blotting and immunohistochemistry.

Results: CHS V effectively attenuated cerebral ischemia/reperfusion (CI/R) injury, including improving neurological deficits, shrinking infarct volume and reducing the number of apoptotic cells. Furthermore, CHS V treatment remarkably increased antioxidant levels and reduced ROS levels and mitochondrial damage by enhancing the expression and deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by activating AMPK and SIRT-1, respectively.

Conclusion: Our data demonstrated that CHS V prevented CI/R injury by suppressing oxidative stress and mitochondrial damage through the modulation of PGC-1α with AMPK and SIRT-1.
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http://dx.doi.org/10.1016/j.phymed.2021.153516DOI Listing
April 2021

LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC.

Mol Ther Nucleic Acids 2021 Mar 9;23:797-810. Epub 2021 Jan 9.

Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.

Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis and and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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http://dx.doi.org/10.1016/j.omtn.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868718PMC
March 2021

Management of Non-Colorectal Digestive Cancers with Microsatellite Instability.

Cancers (Basel) 2021 Feb 6;13(4). Epub 2021 Feb 6.

Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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http://dx.doi.org/10.3390/cancers13040651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915546PMC
February 2021

Nanoliposomal irinotecan (Nal-IRI)-based chemotherapy after irinotecan -based chemotherapy in patients with pancreas cancer.

Pancreatology 2021 Mar 18;21(2):379-383. Epub 2020 Oct 18.

Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA. Electronic address:

Background: Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment for metastatic pancreas cancer. It is unclear, however, whether patients who had received irinotecan derive benefit.

Methods: Medical records of metastatic pancreas cancer patients who had received irinotecan and then Nal-IRI were reviewed. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of >4 months defined success); adverse events and quotes from the medical record on decision-making were also recorded.

Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). The median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 4.3, 5.6 months). An exploratory comparison, based on no cancer progression with irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 5.1, 9.3 months) versus 4.3 months (95% CI: 2.3, 4.8 months); p = 0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrate several themes, including "limited treatment options," which appeared to drive the decision to prescribe Nal-IRI.

Conclusion: Nal-IRI might be considered in pancreas cancer patients who had received irinotecan, particularly in the absence of disease progression with the latter.
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http://dx.doi.org/10.1016/j.pan.2020.10.042DOI Listing
March 2021

Prognostic and Predictive Values of Mismatch Repair Deficiency in Non-Metastatic Colorectal Cancer.

Cancers (Basel) 2021 Jan 15;13(2). Epub 2021 Jan 15.

Division of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN 55905, USA.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Universal MMR/MSI testing is standard of care for all patients with newly diagnosed CRC based on multi-society guidelines in the United States. Such testing is intended to identify patients with Lynch Syndrome due to a germline mutation in an MMR gene, but also detects those with sporadic dMMR/MSI-high CRCs. The prognostic utility of MMR/MSI status in non-metastatic colorectal cancer has been studied extensively, yet more limited data are available for its predictive utility. Results have not been entirely consistent due to potential stage-related differences and limited numbers of dMMR/MSI-H patients included in the studies. In this review, we summarize the current evidence for the prognostic and predictive value of dMMR/MSI-H in non-metastatic CRC, and discuss the use of this biomarker for patient management and treatment decisions in clinical practice.
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http://dx.doi.org/10.3390/cancers13020300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830023PMC
January 2021

Identifying and Meeting the Needs of Adolescents and Young Adults with Cancer.

Curr Oncol Rep 2021 01 15;23(2):17. Epub 2021 Jan 15.

Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, 85054, USA.

Purpose Of Review: Adolescents and young adults (AYAs) with cancer are a vulnerable population with unique needs that are under-recognized and often overlooked by healthcare providers. This review focuses on identifying and meeting some of those needs including adherence to treatment, financial implications, impact on fertility and intimacy, issues with work/school, isolation, challenges with re-entry, and long-term side effects and survivorship.

Recent Findings: Survival rates have not improved in adolescents and young adults with cancer at the same rate as in children and older adults (the so called "AYA gap"). Restricted or delayed access to care and inconsistent cancer treatment and follow-up care contribute to this. Importantly, fertility preservation options have broadened and efforts to provide age appropriate counseling prior to treatment have improved. Additionally, AYAs face a variety of psychosocial issues while dealing with a cancer diagnosis during critical developmental years, and yet data pertaining to the successful identification and management of these issues is lacking. As a result, there has been recent increasing awareness that this patient population warrants strong advocates, additional research, and requires age group specific resources to be successful in navigating their cancer experience during treatment and into survivorship care. Members of the healthcare team should familiarize themselves with the unique needs of AYA cancer patients to provide optimal patient care. In order to build upon early progress, this group calls for additional study particularly when it comes to barriers to enrollment for AYA-specific research (including clinical trials), recognizing psychosocial needs (both during and after treatment), transition planning for returning to life after cancer, and managing long-term effects of treatment (including neuro cognitive changes). In addition, access to financial resources and appropriate mental health support needs to be improved.
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http://dx.doi.org/10.1007/s11912-020-01011-9DOI Listing
January 2021

Contemporary Management of Pancreatic Cancer from an Internist Perspective.

Am J Med 2021 05 11;134(5):576-586. Epub 2020 Dec 11.

Mayo Clinic, Phoenix, Ariz.

Primary care physicians are in a favorable position to curb the growing burden of pancreatic ductal adenocarcinoma. This review aims to provide an overview of pancreatic ductal adenocarcinoma from a primary care perspective, with a specific focus on risk factors, selection of high-risk individuals for screening, patient presentation at the primary-care clinic, and the role of the internist in supportive care. Overall, the internist is an essential member of the multidisciplinary care team with respect to optimizing patients' quality of life across various stages of the pancreatic cancer.
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http://dx.doi.org/10.1016/j.amjmed.2020.11.009DOI Listing
May 2021

Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors.

Cancer Discov 2020 12 2;10(12):1808-1825. Epub 2020 Nov 2.

Departments of Medicine and Gastrointestinal Research Unit, Mayo Clinic, Rochester, Minnesota.

Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel sequencing-based estimates of TMB have largely replaced whole-exome sequencing-derived TMB in the clinic. Retrospective evidence suggests that TMB can predict the efficacy of immune checkpoint inhibitors, and data from KEYNOTE-158 led to the recent FDA approval of pembrolizumab for the TMB-high tumor subgroup. Unmet needs include prospective validation of TMB cutoffs in relationship to tumor type and patient outcomes. Furthermore, standardization and harmonization of TMB measurement across test platforms are important to the successful implementation of TMB in clinical practice. SIGNIFICANCE: Evaluation of TMB as a predictive biomarker creates the need to harmonize panel-based TMB estimation and standardize its reporting. TMB can improve the predictive accuracy for immunotherapy outcomes, and has the potential to expand the candidate pool of patients for treatment with immune checkpoint inhibitors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710563PMC
December 2020

Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis.

JAMA Oncol 2020 12 10;6(12):e204930. Epub 2020 Dec 10.

Mayo Clinic Cancer Center, Phoenix, Arizona.

Importance: The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.

Objective: To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.

Data Sources: We searched various databases for abstracts and full-text articles published from database inception through March 2020.

Study Selection: We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting.

Data Extraction And Synthesis: The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model.

Main Outcomes And Measures: Outcomes of interest included overall (OS) and progression-free survival (PFS).

Findings: Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.

Conclusions And Relevance: This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.
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http://dx.doi.org/10.1001/jamaoncol.2020.4930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582230PMC
December 2020

Investigating the Fate of MP1000-LPX by Adding Serum to Transfection Medium.

Pharm Nanotechnol 2020 ;8(5):399-408

Department of Pharmacy, West China School of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.

Background: Cationic liposomes (CLs) based messenger RNA (mRNA) vaccine has been a promising approach for cancer treatment. However, rapid lung accumulation after intraveous injection and significantly decreased transfection efficacy (TE) in serum substantially hamper its application.

Objective: In this study, we attempt to investigate the fate of Mannose-PEG1000-lipoplex (MP1000-LPX) in vivo, a previous reported mRNA vaccine, and potential mechanism in it.

Methods: MP1000-CLs and different type of MP1000-LPX were produced by previous method and characterized by dynamic light scattering (DLS). Organ distribution and Luc-mRNA expression of DiD loaded luciferase (Luc-mRNA)-MP1000-LPX were evaluated by IVIS Spectrum imaging system. Cellular transfection and uptake under serum-free and serum-containing conditions were analysed by flow cytometry and counted by FlowJo software.

Results: MP1000-CLs had an average size of 45.3 ± 0.9 nm, a positive charge of 39.9 ± 0.9 mV. When MP1000-LPX formed, the particle size increased to about 130 nm, and zeta potential decreased to about 30 mV. All formulations were in narrow size distribution with PDI < 0.3. 6 h after intraveous injection, Luc-MP1000-LPX mostly distributed to liver, lung and spleen, while only successfully expressed Luc in lung. DC2.4 cellular transfection assay indicated serum substantially lowered TE of MP1000-LPX. However, the cellular uptake on DC2.4 cells was enhanced in the presence of serum.

Conclusion: MP1000-LPX distributed to spleen but failed to transfect. Because serum dramatically decreased TE of MP1000-LPX on DC2.4 cells, but not by impeding its interaction to cell membrane. Serum resistance and avoidance of lung accumulation might be prerequisites for CLs based intravenous mRNA vaccines. Lay Summary: mRNA vaccine has been promising immunotherapy to treat cancer by delivering mRNA encoding tumor antigens to APCs and activating immune system against tumor cells. We are investigating the in vivo fate of MP1000-LPX, a CLs based mRNA vaccine. To see if serum causes the fate, we'll be looking at the influence of serum on transfection and uptake efficacy of MP1000-LPX by DC2.4 cells experiments in vitro. Our findings will imply that serum inhibits transfection but not by decreasing uptake. Thus, we can ultilize serum to enhance transfection if we make intracellular process of MP1000-LPX successful.
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http://dx.doi.org/10.2174/2211738508666200907105224DOI Listing
January 2020

Tumor suppressor role of miR-876-5p in gastric cancer.

Oncol Lett 2020 Aug 28;20(2):1281-1287. Epub 2020 May 28.

Healthy Food Evaluation Center, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Gastric cancer (GC) is the second most common cancer cause of cancer-related mortality worldwide. Recent studies have demonstrated the function of microRNAs (miRNAs) in the pathogenesis of GC. miR-876-5p demonstrated an antitumor role in hepatocellular carcinoma and lung cancer; however, the function of miR-876-5p has not yet been fully identified in GC. Thus, the present study aimed to investigate the role of miR-876-5p in GC. The results of the present study demonstrated low expression levels of miR-876-5p in GC tumor tissues. Furthermore, overexpression of miR-876-5p inhibited GC cell proliferation and promoted apoptosis, whilst miR-876-5p knockdown promoted GC cell proliferation and decreased cisplatin sensitivity of GC cells. Transforming growth factor β-receptor 1 was demonstrated to be a potential target gene of miR-876-5p. Overall, the results of the present study suggest that miR-876-5p plays an antitumor role in GC.
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http://dx.doi.org/10.3892/ol.2020.11680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377156PMC
August 2020

A randomized double-blind placebo-controlled multicenter trial of Bushen Yisui and Ziyin Jiangzhuo formula for constipation in Parkinson disease.

Medicine (Baltimore) 2020 Jul;99(28):e21145

Parkinson Medical Center, Beijing Rehabilitation Hospital, Capital Medical University.

Introduction: Constipation is a common nonmotor symptom of Parkinson disease (PD). Constipation can also impact patient's quality of life. Chinese herbal medicines have been used for the treatment of constipation in PD. This trial will evaluate the efficacy and safety of a Chinese herbal formula Bushen Yisui and Ziyin Jiangzhuo (BYZJ) for the treatment of constipation in PD.

Methods And Analysis: This randomized, double-blind, placebo-controlled, multicenter clinical trial will involve 4 hospitals in Beijing, China. The study will aim to recruit 90 PD patients with constipation between 30 and 80 years-of age with a score of 1 - 4 on the Hoehn and Yahr scale. Once recruited, Patients will be randomized into a BYZJ group or a placebo group in a 2:1 ratio. The trial will include a 1-week run-in period, a 4-week double-blind treatment period, a 4-week and a 12-week follow-up period. All patients will be educated about PD-related constipation during the run-in period. BYZJ granules and simulated granules will be administered twice daily for 4 weeks to the BYZJ group and the placebo group respectively. Assessments will be performed during run-in period, before the start of treatment (baseline, week 0), and at 4, 8, and 16 weeks. The primary outcome will be measured with the Constipation Severity Instrument, and secondary outcomes will be evaluated with the Patient Assessment of Constipation Quality of Life questionnaire, Bristol Stool Form Scale, Movement Disorders-Unified Parkinson Disease Rating Scale, Nonmotor Symptoms Scale, PD Sleep Scale, Parkinson Fatigue Scale-16. Laxative use (dose and frequency) will also be recorded. Intention-to-treat and per-protocol set analyses will be used to compare symptom improvement between the 2 groups. Any adverse events will be recorded.

Discussion: If found effective and safe, BYZJ formula will be one of Chinese herb to treat constipation and even other nonmotor or motor symptoms in PD patients. The results will sustain the broader use of BYZJ formula in PD.
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http://dx.doi.org/10.1097/MD.0000000000021145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360320PMC
July 2020

Falls: descriptive rates and circumstances in age-unspecified patients with locally advanced esophageal cancer.

Support Care Cancer 2021 Feb 24;29(2):733-739. Epub 2020 May 24.

Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Purpose: Falls can occur in older cancer patients, but few studies have examined falls in an age-unspecified group of patients with locally advanced esophageal cancer. Because these patients are often administered neuropathy-inducing agents, are weak, and can develop orthostatic symptoms, examining falls appears relevant.

Methods: Electronic medical records were used to examine falls and their circumstances in locally advanced esophageal cancer patients treated with chemotherapy and radiation and often surgery.

Results: Among 300 patients, 62 (21%) suffered a fall, yielding 6 falls per 100 patient years. The median age at first fall was 64 years (range 31 to 83). The median time from cancer diagnosis to first fall was 11 months (range 0 to 107). Forty-two patients (68%) who fell had active cancer; 20 (32%) were cancer-free. Fall-related injuries occurred in 42 patients and included fractures, hematomas, and other musculoskeletal events. Eighteen patients (29%) fell repeatedly. Neuropathy, general weakness, and orthostatic symptoms were associated with falls ("He does state his neuropathy is more bothersome…. He did have a fall last week…." "He has been increasingly weak to the point where he fell down last week…." "Upon rising… [he] felt like somebody had put a sheet over his eyes, felt very lightheaded, and fell to the floor…."). At times, falls occurred under commonplace circumstances, such as slipping on ice or tripping on an underfoot pet.

Conclusion: Regardless of patient age, clinicians should remain vigilant for fall risk in adult patients with locally advanced esophageal cancer.
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http://dx.doi.org/10.1007/s00520-020-05511-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683374PMC
February 2021

Multicolor tunable luminescence and energy transfer of core-shell structured [email protected] microspheres co-activated with Dy/Eu under single UV excitation.

Dalton Trans 2020 Jun 19;49(22):7397-7405. Epub 2020 May 19.

Analysis and Testing Center, Jilin Institute of Chemical Technology, Jilin 132022, China.

Optimizing structure and varying doped ions are two main strategies to obtain excellent luminescence performance. Spherical morphology is considered to be the most ideal phosphor structure due to the least surface defects. Herein, a series of spherical and monodispersed Dy/Eu co-activated [email protected] core-shell phosphors with multicolor tunable luminescence were successfully prepared via a facile urea assisted precipitation method. Related chemical reactions and the possible growth mechanism of GdO:Ln directional deposition on the surface of SiO microspheres were put forward. Upon 273 nm UV radiation excitation, [email protected]:Dy and [email protected]:Eu samples exhibited characteristic yellow (F-H) and blue (F-H) emissions of Dy and red (D-F) emission of Eu, respectively. Meanwhile, multicolor emissions (warm white, yellow and orange) could be easily obtained by modulating the relative content of Dy and Eu in [email protected]:Ln samples under a single excitation wavelength. Moreover, it was confirmed that Dy could transfer energy to Eu in the form of quadrupole-quadrupole interaction and further improved the luminescence intensity of Eu by comparing experimental data with theoretical calculations. These results imply that tunable luminescence Dy,Eu co-doped [email protected] microspheres have great potential applications in multicolor displays and biolabeling fields.
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http://dx.doi.org/10.1039/d0dt00735hDOI Listing
June 2020

Survival and prognostic factors in patients with rectal squamous cell carcinoma.

Eur J Surg Oncol 2020 06 4;46(6):1111-1117. Epub 2020 Mar 4.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Squamous cell carcinoma (SCC) of the rectum is a rare form of gastrointestinal malignancy. The current knowledge on the natural history is primarily derived from case series.

Methods: Using the National Cancer Data Base (NCDB), we determined the prognostic factors and overall survival (OS) outcomes of rectal SCC reported to NCDB between 2004 and 2015. Kaplan-Meier method and log-rank test were used to perform OS analysis. Propensity matched analysis was undertaken to compare the OS outcomes between rectal and anal SCC.

Results: Of the 3405 cases included in our analysis, 67% were female. Median age at diagnosis was 61 years and did not differ by sex. In stages I-III, patients who received definitive chemoradiation only (108 months) had a better median OS as compared to surgery alone (76 months) (p = 0.012). On multivariate analysis, age <60 years, female sex, and receipt of chemoradiation with or without surgery were independent predictors of better OS in stage I-III disease. Administration of chemoradiation was associated with better OS in stage IV disease. On propensity matched analysis comparing outcomes to anal SCC, OS of rectal SCC was inferior (79 months) to anal SCC (113 months) (p < 0.001), no such difference in OS was noted in the cohorts that received surgery plus post-surgical chemoradiation (p = 0.12).

Conclusion: Outcomes of rectal SCC were dependent upon age, sex, comorbidity score, and therapy received. Chemoradiation alone or in combination with surgery was associated with a better median OS in patients with stages I-III.
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http://dx.doi.org/10.1016/j.ejso.2020.02.039DOI Listing
June 2020

Evaluating the Safety and Efficacy of Nivolumab in Patients with Advanced Hepatocellular Carcinoma: Evidence to Date.

Onco Targets Ther 2019 28;12:10335-10342. Epub 2019 Nov 28.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Surgical resection of the primary lesion, liver-directed therapies, and orthotropic liver transplantation are employed in localized disease depending upon the clinical status, underlying liver function, the size, and location of the liver lesions. Systemic therapy plays a critical role in the management of advanced HCC. Sorafenib had remained as the only United States Food and Drug Administration (US-FDA)-approved systemic therapeutic agent for approximately a decade since its approval in 2007, until the advent of immunotherapy and a better understanding of HCC molecular pathogenesis changed the landscape of advanced HCC management. Lenvatinib was approved as an alternative first-line agent, whereas regorafenib, nivolumab, pembrolizumab, ramucirumab, and cabozantinib were approved as second-line agents for HCC patients who could not tolerate or whose disease progressed on sorafenib. Nivolumab and pembrolizumab are the two immunotherapeutic agents that were conditionally approved by the US-FDA based on the encouraging results in Phase I/II trials. This review discusses the potential role of immunotherapy in advanced HCC with a special focus on nivolumab.
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http://dx.doi.org/10.2147/OTT.S214870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886547PMC
November 2019

Inhibition of cancer cell growth in gemcitabine-resistant pancreatic carcinoma by mangiferin phytochemical involves induction of autophagy, endogenous ROS production, cell cycle disruption, mitochondrial mediated apoptosis and suppression of cancer cell migration and invasion.

J BUON 2019 Jul-Aug;24(4):1581-1586

Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China.

Purpose: Pancreatic cancer causes considerable mortality across the globe and the treatment options for pancreatic cancer are limited. Besides, the development of drug resistance among the pancreatic cancer cells makes it even difficult to manage. In this study the anticancer effects of mangiferin were examined against the Mia-PaCa2 gemcitabine-resistant pancreatic cancer cells.

Materials/methods: Cell proliferation was examined by MTT assay while as apoptosis was detected by fluorescent microscopy and western blot. Effects on cell cycle, reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were evaluated by flow cytometry. The fact that mangiferin induced autophagy was demonstrated by fluorescent microscopy in combination with western blot method.

Results: The results revealed that mangiferin inhibited the growth of the Mia-PaCa2 cells and exhibited an IC50 of 10 µM. Nonetheless, the toxic effects of mangiferin were less on the normal cells. Mangiferin induces apoptosis in the Mia-PaCa2 cells which was associated with enhancement of Bax/Bcl-2 ratio. Further investigations revealed that mangiferin triggered autophagy in the Mia-PaCa2 cells as evident from the elevated expressions of the LC3 II and Beclin-1. The antiproliferative effects of mangiferin were also accompanied by the generation of endogenous ROS and cell cycle arrest. Investigation of the effects of mangiferin on the invasion and migration of the Mia-PaCa2 cells showed that mangiferin suppressed the migration and invasion potential of the Mia-PaCa2 cells.

Conclusions: These findings suggest that mangiferin could be utilised for the development of chemotherapy for pancreatic cancer provided further in depth experiments are carried out along with its toxicological studies.
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March 2020

A Pandas complex adapted for piRNA-guided transcriptional silencing and heterochromatin formation.

Nat Cell Biol 2019 10 30;21(10):1261-1272. Epub 2019 Sep 30.

Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila, Panoramix enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occurs remain elusive. Here, we show that Panoramix functions together with a germline-specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15), to suppress transposon expression. The transposon RNA-binding protein dNxf2 is required for animal fertility and Panoramix-mediated silencing. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. The NTF2 domain of dNxf2 competes dNxf1 (TAP) off nucleoporins, a process required for proper RNA export. Thus, dNxf2 functions in a Panoramix-dNxf2-dependent TAP/p15 silencing (Pandas) complex that counteracts the canonical RNA exporting machinery and restricts transposons to the nuclear peripheries. Our findings may have broader implications for understanding how RNA metabolism modulates heterochromatin formation.
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http://dx.doi.org/10.1038/s41556-019-0396-0DOI Listing
October 2019

Label-Free Electrochemical Immunosensor Based on a Functionalized Ionic Liquid and Helical Carbon Nanotubes for the Determination of Cardiac Troponin I.

ACS Omega 2019 Jul 9;4(7):11888-11892. Epub 2019 Jul 9.

Department of Chemistry and Pharmaceutical Engineering and Department of Petrochemical Technology, Jilin Institute of Chemical Technology, Jilin 132022, P. R. China.

A label-free electrochemical immunosensor for cardiac troponin I was prepared by using a helical carbon nanotube-supported aldehyde-functionalized ionic liquid. Because of the good conductivity of ionic liquid and helical carbon nanotubes, high sensitivity of the immunosensor was obtained. Functionalized ionic liquid provided binding sites for antibody, which simplified the process of sensor construction. Cardiac troponin I was detected by this immunosensor with a linear range of 0.05-30 ng/mL and a detection limit of 0.03 ng/mL. The electrochemical immunosensor had satisfactory reproducibility, high sensitivity, and acceptable specificity.
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http://dx.doi.org/10.1021/acsomega.9b01152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682139PMC
July 2019

Advances in the therapy of BRAF metastatic colorectal cancer.

Expert Rev Anticancer Ther 2019 09 4;19(9):823-829. Epub 2019 Sep 4.

Division of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center , Rochester , MN , USA.

: metastatic colorectal cancer (CRC) is an aggressive tumor subset with an approximate 8% incidence. In these patients, standard chemotherapy has limited efficacy, and the recent development of novel-targeted treatment regimens may significantly improve clinical outcome. : This review provides an overview of available data regarding advances in the first-line treatment of metastatic CRC including patient tumors with microsatellite instability. The implications of in earlier stage CRC are also discussed. : Recently, significant progress has been achieved in improving tumor response rates using a novel-targeted regimen in patients with metastatic CRC. The implications of in non-metastatic CRC are also becoming more evident and remains an area of ongoing investigation. The majority of CRCs with microsatellite instability high are sporadic and frequently harbor . All patients with microsatellite instability high metastatic CRCs, irrespective of , are candidates for immune checkpoint inhibitors. The optimal sequencing of treatment regimens for patients with metastatic CRCs is an important area for future research.
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http://dx.doi.org/10.1080/14737140.2019.1661778DOI Listing
September 2019

Novel Prognostic Factors in Resected Small Bowel Adenocarcinoma.

Clin Colorectal Cancer 2019 09 15;18(3):218-225. Epub 2019 May 15.

Division of Medical Oncology, Mayo Clinic, Rochester, MN. Electronic address:

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy affecting approximately 3000 patients per year in the United States, and there is limited evidence prognosticating patients with resected SBA. We aimed to evaluate prognostic factors and the role of adjuvant therapy in patients with resected SBA.

Patients And Methods: Two hundred forty-one patients who had resected stage I-III SBA were retrospectively identified at a single tertiary referral institution. Overall survival (OS) analysis was performed by the Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed to identify significant variables by univariate and multivariate analysis.

Results: Median OS for the entire group was 54.5 months (95% confidence interval [CI], 37.2-81.2 months), with 5- and 10-year OS of 48% and 35%. Median follow-up was 113.7 months (95% CI, 97.9-126.6 months). For patients with stage III disease who received adjuvant therapy, the median OS was 33.8 months (95% CI, 27.8-78.8) compared to 24.7 months (95% CI, 11.5-37.8) for patients with no adjuvant therapy (P < .01). Male sex, advanced T stage, advanced N stage, increased positive lymph node ratio, lymphocyte-to-monocyte ratio < 1.56, presence of residual disease, and earlier date of diagnosis predicted worse survival on univariate analysis. Age > 60 years, lymphocyte-to-monocyte ratio < 1.56, and advanced T stage were identified as independent negative predictors of OS for all patients by multivariate analysis.

Conclusion: Advanced age, advanced T stage, and lymphocyte-to-monocyte ratio < 1.56 independently predicted survival in resected SBA. Adjuvant therapy is associated with improved survival in patients with resected stage III SBA.
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http://dx.doi.org/10.1016/j.clcc.2019.05.002DOI Listing
September 2019

Local excision for patients with stage I anal canal squamous cell carcinoma can be curative.

J Gastrointest Oncol 2019 Apr;10(2):171-178

Department of Medical Oncologyy, Mayo Clinic, Rochester, MN, USA.

Background: Definitive concurrent chemoradiation is the current standard of care for all stage I anal canal squamous cell carcinoma. Local excision as primary treatment for selected stage I lesions has been reported in the literature but is not currently recommended by major guidelines. We herein compared the oncologic outcomes of patients with stage I anal canal squamous cell carcinoma treated with local excision alone versus chemoradiation to determine if there are any significant differences in outcomes including disease free survival, overall survival (OS) and local failure rate.

Methods: A retrospective review of all patients treated for stage I anal canal squamous cell carcinoma between 1990 and 2016 was conducted. Data collected included baseline demographics, staging studies, pathology, treatment received, relapse pattern and survival.

Results: A total of 57 patients were treated for stage I anal canal squamous cell carcinoma between 1990 and 2016; 13 were treated with local excision alone and 44 were treated with chemoradiation therapy. Baseline characteristics in both cohorts of patients were comparable. Median follow-up duration of the local excision and the chemoradiation cohorts were 106 and 70 months, respectively. Of the 13 patients in local excision cohort, two patients had disease recurrence, at 21 and 97 months from the diagnosis. Both patients were long term survivors with salvage treatment. In chemoradiation cohort, 1 out of 44 patients had a local recurrence at 1 year who underwent curative resection. Five-year progression free survival (PFS) of subjects in local excision cohort and chemoradiation cohort were 91% and 83%, respectively (P=0.57).

Conclusions: Local excision as primary treatment may be safe and effective for a selected group of stage I anal canal squamous cell carcinoma patients.
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http://dx.doi.org/10.21037/jgo.2018.12.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465491PMC
April 2019

Solid Pseudopapillary Neoplasms of the Pancreas: A Large American Cohort.

Pancreas 2019 04;48(4):e21-e22

Division of Medical Oncology Mayo Clinic Rochester, MN Department of Oncology Clinica Santa Maria Santiago, Chile Department of Internal Medicine Mayo Clinic Rochester, MN Division of Medical Oncology Mayo Clinic Rochester, MN Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN Division of Medical Oncology Mayo Clinic Rochester, MN

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http://dx.doi.org/10.1097/MPA.0000000000001288DOI Listing
April 2019

Supersonic Screw Dislocations Gliding at the Shear Wave Speed.

Phys Rev Lett 2019 Feb;122(4):045501

Institute of Applied Mechanics and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China.

The motion of dislocations bridges the atomistic-scale deformation events with the macroscopic strength and ductility of crystalline metals. In particular, screw dislocations, whose Burgers vector is parallel to the line, play crucial roles on plastic flow. Nevertheless, their speed limit and its stress dependence remain controversial. Using large-scale molecular dynamics simulations, we reveal that full screw dislocations and twinning partial screw-type dislocations can glide steadily at the speed of shear wave velocity. Such a scenario is excluded in existing theories due to energy dissipation singularity. We conclude that both types of screw dislocations can move supersonically. We further observe that the motion of a screw dislocation also depends on the shear stress components, which do not contribute to the resolved shear stress (RSS), in contrast to the conventional Schmid's law, which states that the motion of a dislocation is determined by the RSS.
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http://dx.doi.org/10.1103/PhysRevLett.122.045501DOI Listing
February 2019

Identification of Adenosquamous Carcinoma as a Rare Aggressive HER2-negative Subgroup of Esophageal/Gastroesophageal Junction Adenocarcinoma.

Am J Clin Oncol 2019 02;42(2):190-195

Mayo Clinic, Rochester, MN.

Background: Our purpose was to evaluate the prognostic impact of pathologically confirmed esophageal adenosquamous carcinoma (ASC) and its association with HER2 status and clinicopathologic characteristics.

Methods: Among 796 patients with esophageal or gastroesophageal junction adenocarcinoma who underwent curative resection, surgical pathology reports were reviewed, and suspected ASC was confirmed utilizing p63 and CK5/6 immunostaining. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization. Cox models were used to assess the impact of ASC on disease-specific survival and overall survival.

Results: Overall, 2.0% (16/796) of patients had esophageal ASC, mostly demonstrating a close intermingling of squamous and adenocarcinoma cells within the same tumor. The percentage of squamous versus adenocarcinoma cells in the primary was generally recapitulated in nodal metastases, and intrapatient internodal heterogeneity was uncommon. Patients with esophageal ASC were statistically significantly more likely to be female (vs. male), have normal (vs. excess) body mass index, and harbor HER2-negative (vs. positive) tumors, as compared with patients with adenocarcinoma only. No ASC tumor was HER2-positive as compared with 16% of adenocarcinoma only tumors (P=0.018). Compared with patients with adenocarcinoma only, those with ASC demonstrated profoundly worse disease-specific survival (5-year event-free rate, 34% vs. 6%; multivariate hazard ratio, 2.87 [95% confidence interval, 1.59-4.76]; P=0.0010) and overall survival (P=0.0027) that was independent of known prognostic factors and HER2 status.

Conclusion: ASC identifies a rare aggressive HER2-negative subgroup of esophageal/gastroesophageal junction adenocarcinoma.
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http://dx.doi.org/10.1097/COC.0000000000000495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546176PMC
February 2019

Folate-Modified Liposomes Loaded with Telmisartan Enhance Anti-Atherosclerotic Potency for Advanced Atherosclerosis in ApoE Mice.

J Biomed Nanotechnol 2019 Jan;15(1):42-61

For the effective inhibition of atherosclerotic plaque rupture, there is an urgent need to develop a carrier which can specifically deliver the therapeutic agents to atherosclerotic lesions. Since the representative hallmark of plaques in advanced atherosclerosis is the large number of macrophages which highly upregulate folate receptor beta (FR-), we herein investigated the potential of folate-modified liposomes (FA-P-LP) as the carrier for active targeting of atherosclerotic plaques. cellular uptake tests, FA-P-LP exhibited an enhanced uptake in activated RAW264.7 macrophages with high expression of FR-, whereas this enhanced effect was dramatically diminished when the cells were pretreated with excess amount of free folate, indicating that FA-P-LP were mainly taken up by the receptor-mediated endocytosis. From the distribution assay, it was confirmly demonstrated that FA-P-LP significantly accumulated in atherosclerotic lesions and were co-localized with macrophages within plaques. Thereafter, we utilized the FA-P-LP to deliver an angiotensin receptor blocker (ARB), telmisartan (Tel), to macrophages in atherosclerotic plaques and evaluated their therapeutic effects on plaque destabilization. After 12 weeks treatment in ApoE mice with established atherosclerosis, FA-P-LP/Tel exerted a marked improvement in key advanced plaque properties without affecting the plasma lipid level and blood pressure. These beneficial effects include the regression of atherosclerotic plaques possibly attributing to the enhanced cellular cholesterol efflux and reduced macrophage infiltration, an increase in the protective collagen layer overlying lesions resulting from suppression of collagenase activity and decrease in matrix 2/9 (MMP 2/9) expression, suppression of oxidative stress, and a reduction in plaque necrosis and calcification. Thus, administration of Tel in a targeted liposome could stabilize the advanced atherosclerotic lesions independent of lipid lowering and blood pressure decrease. In conclusion, FA-P-LP could effectively home to the atherosclerotic lesion through the active targeting mechanism after systemic administration, indicating their high potential as the carrier for atherosclerosis therapy. Together, the FA-P-LP/Tel would be considered as a promising nanotherapeutic approach to prevent plaque rupture, providing an alternative regimen for clinical treatment of advanced atherosclerosis.
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http://dx.doi.org/10.1166/jbn.2019.2676DOI Listing
January 2019
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