Publications by authors named "William Chen"

280 Publications

PPARα Agonist Fenofibrate Attenuates Iron Induced Liver Injury in Mice by Modulating the Sirt3 and β-catenin Signaling.

Am J Physiol Gastrointest Liver Physiol 2021 07 21. Epub 2021 Jul 21.

Department of Ophthalmology, Saint Louis University, St Louis, MO, United States.

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/β-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator activated receptor alpha (PPARα) agonist, fenofibrate prevents iron induced oxidative stress and β-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD-dependent deacetylase that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury by normalizing the Wnt/β-catenin pathway. In the present study, we explored if fenofibrate prevents iron induced liver injury by regulating the Sirt3 and β-catenin signaling. In-vitro and in-vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active β-catenin and its downstream target gene c-Myc in the mouse liver. Pharmacological activation of Sirt3, both invitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active β-catenin expression and prevented the iron induced upregulation of αSMA and TGFβ expression. Intrinsically, PPARα KO mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron induced downregulation of liver Sirt3 and active β-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3 and β-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron induced liver injury likely has significant therapeutic impact on iron associated chronic liver diseases.
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http://dx.doi.org/10.1152/ajpgi.00129.2021DOI Listing
July 2021

In silico model for miRNA-mediated regulatory network in cancer.

Brief Bioinform 2021 Jul 19. Epub 2021 Jul 19.

Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA.

Deregulation of gene expression is associated with the pathogenesis of numerous human diseases including cancer. Current data analyses on gene expression are mostly focused on differential gene/transcript expression in big data-driven studies. However, a poor connection to the proteome changes is a widespread problem in current data analyses. This is partly due to the complexity of gene regulatory pathways at the post-transcriptional level. In this study, we overcome these limitations and introduce a graph-based learning model, PTNet, which simulates the microRNAs (miRNAs) that regulate gene expression post-transcriptionally in silico. Our model does not require large-scale proteomics studies to measure the protein expression and can successfully predict the protein levels by considering the miRNA-mRNA interaction network, the mRNA expression, and the miRNA expression. Large-scale experiments on simulations and real cancer high-throughput datasets using PTNet validated that (i) the miRNA-mediated interaction network affects the abundance of corresponding proteins and (ii) the predicted protein expression has a higher correlation with the proteomics data (ground-truth) than the mRNA expression data. The classification performance also shows that the predicted protein expression has an improved prediction power on cancer outcomes compared to the prediction done by the mRNA expression data only or considering both mRNA and miRNA. Availability: PTNet toolbox is available at http://github.com/CompbioLabUCF/PTNet.
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http://dx.doi.org/10.1093/bib/bbab264DOI Listing
July 2021

IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats.

Aging (Albany NY) 2021 07 7;13(13):17536-17547. Epub 2021 Jul 7.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan.

Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.
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http://dx.doi.org/10.18632/aging.203244DOI Listing
July 2021

High-throughput 5' UTR engineering for enhanced protein production in non-viral gene therapies.

Nat Commun 2021 07 6;12(1):4138. Epub 2021 Jul 6.

Synthetic Biology Group, Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA.

Despite significant clinical progress in cell and gene therapies, maximizing protein expression in order to enhance potency remains a major technical challenge. Here, we develop a high-throughput strategy to design, screen, and optimize 5' UTRs that enhance protein expression from a strong human cytomegalovirus (CMV) promoter. We first identify naturally occurring 5' UTRs with high translation efficiencies and use this information with in silico genetic algorithms to generate synthetic 5' UTRs. A total of ~12,000 5' UTRs are then screened using a recombinase-mediated integration strategy that greatly enhances the sensitivity of high-throughput screens by eliminating copy number and position effects that limit lentiviral approaches. Using this approach, we identify three synthetic 5' UTRs that outperform commonly used non-viral gene therapy plasmids in expressing protein payloads. In summary, we demonstrate that high-throughput screening of 5' UTR libraries with recombinase-mediated integration can identify genetic elements that enhance protein expression, which should have numerous applications for engineered cell and gene therapies.
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http://dx.doi.org/10.1038/s41467-021-24436-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260622PMC
July 2021

An Advanced Magnetic Resonance Imaging and Ultrasonic Theranostics Nanocomposite Platform: Crossing the Blood-Brain Barrier and Improving the Suppression of Glioblastoma Using Iron-Platinum Nanoparticles in Nanobubbles.

ACS Appl Mater Interfaces 2021 Jun 2;13(23):26759-26769. Epub 2021 Jun 2.

Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.

Glioblastoma (GBM) is one of the deadliest and most invasive brain cancers/gliomas, and there is currently no established way to treat this disease. The treatment of GBM typically involves intracranial surgery followed by chemotherapy. However, the blood-brain barrier (BBB) impedes the delivery of the chemotherapeutic drug, making the treatment challenging. In this study, we embedded a chemotherapeutic drug and other nanomaterials into a nanobubble (NB), utilized active tracking and other guidance mechanisms to guide the nanocomposite to the tumor site, and then used high-intensity focused ultrasound oscillation to burst the nanobubbles, generating a transient cavitation impact on the BBB and allowing the drug to bypass it and reach the brain. FePt enhances the resolution of T2-weighted magnetic resonance imaging images and has magnetic properties that help guide the nanocomposite to the tumor location. FePt nanoparticles were loaded into the hydrophobic core of the NBs along with doxorubicin to form a bubble-based drug delivery system ([email protected]). The surface of the NBs is modified with a targeting ligand, transferrin ([email protected]), giving the nanocomposite active tracking abilities. The [email protected] developed in the present study represents a potential breakthrough in GBM treatment through improved drug delivery and biological imaging.
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http://dx.doi.org/10.1021/acsami.1c04990DOI Listing
June 2021

An independent predictor of poor prognosis in locally advanced rectal cancer: rs867228 in formyl peptide receptor 1 (FPR1).

Oncoimmunology 2021 May 14;10(1):1926074. Epub 2021 May 14.

School of Medicine, China Medical University, Taichung Taiwan.

Formyl peptide receptor 1 (FPR1) plays a key regulatory role in innate and adaptive immunity. Recently, we reported that the CC genotype of FPR1-E346A (rs867228, c. 1037 A > C) is an independent biomarker for patients with locally advanced rectal cancer (LARC) who received preoperative concurrent chemoradiotherapy (CCRT). Pharmacologic inhibition of FPR1 decreased the migration and infiltration of T lymphocytes into tumor microenvironment after CCRT.
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http://dx.doi.org/10.1080/2162402X.2021.1926074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128175PMC
May 2021

Efficacy and safety of magnetic resonance-guided focused ultrasound for the treatment of painful bone metastases: a systematic review and meta-analysis.

Skeletal Radiol 2021 May 21. Epub 2021 May 21.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Lobby 6, Suite 350, San Francisco, CA, 94107, USA.

Objective: To report the safety and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) in the treatment of painful bone metastases through a systematic review and meta-analysis of pain scores before and after MRgFUS treatment and post-treatment adverse events.

Materials And Methods: A comprehensive literature search of PubMed and Embase databases was performed for studies evaluating the efficacy and/or safety of MRgFUS. The mean difference of pain scores (10-point visual analogue scale or numerical rating scale) between baseline and 1-month/3-month pain scores was collected and analyzed in a pooled meta-analysis. Post-treatment adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) grading were recorded and the pooled prevalence was calculated.

Results: A total of 33 studies published between 2007 and 2019 were collected, resulting in a total sample size of 1082 patients. The majority of the studies were prospective with a reported follow-up period of 3 months. The pooled proportion of patients that achieved pain relief from MRgFUS (complete response or partial response [≥ 2-point improvement of pain score]) was 79% (95% CI 73-83%). The pooled 1-month and 3-month mean difference in pain score were - 3.8 (95% CI - 4.3; - 3.3) and - 4.4 (95% CI - 5.0; - 3.7), respectively. The overall rate of high-grade (CTCAE grade 3 or higher) and low-grade (CTCAE grade 2 or lower) MRgFUS-related adverse events were 0.9% and 5.9%, respectively.

Conclusion: MRgFUS is an effective procedure that is able to provide significant pain palliation for patients with symptomatic bone metastases with a favorable safety profile.
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http://dx.doi.org/10.1007/s00256-021-03822-8DOI Listing
May 2021

Efficacy and Safety of Stereotactic Radiosurgery for Brainstem Metastases: A Systematic Review and Meta-analysis.

JAMA Oncol 2021 Jul;7(7):1033-1040

Department of Radiation Oncology, University of California, San Francisco.

Importance: Owing to the proximity to critical neurologic structures, treatment options for brainstem metastases (BSM) are limited, and BSM growth can cause acute morbidity or death. Stereotactic radiosurgery (SRS) is the only local therapy for BSM, but efficacy and safety of this approach are incompletely understood because patients with BSM are excluded from most clinical trials.

Objective: To perform a systematic review and comparative meta-analysis of SRS studies for BSM in the context of prospective trials of SRS or molecular therapy for nonbrainstem brain metastases (BM).

Data Sources: A comprehensive search of Pubmed/MEDLINE and Embase was performed on December 6, 2019.

Study Selection: English-language studies of SRS for BSM with at least 10 patients and reporting 1 or more outcomes of interest were included. Duplicate studies or studies with overlapping data sets were excluded. Studies were independently evaluated by 2 reviewers, and discrepancies were resolved by consensus. A total of 32 retrospective studies published between 1999 and 2019 were included in the analysis.

Data Extraction And Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify studies. Study quality was assessed using Methodological Index for Non-Randomized Studies criteria. Fixed and random-effects meta-analyses and meta-regressions were performed for the outcomes of interest.

Main Outcomes And Measures: Primary study outcomes included 1-year and 2-year local control and overall survival, objective response rate, symptom response rate, neurological death rate, and rate of grade 3 to 5 toxic effects as described in Common Terminology Criteria for Adverse Events, version 4.0.

Results: The 32 retrospective studies included in the analysis comprised 1446 patients with 1590 BSM that were treated with SRS (median [range] dose, 16 [11-39] Gy; median [range] fractions, 1 [1-13]). Local control at 1 year was 86% (95% CI, 83%-88%; I2 = 38%) in 1410 patients across 31 studies, objective response rate was 59% (95% CI, 47%-71%; I2 = 88%) in 642 patients across 17 studies, and symptom improvement was 55% (95% CI, 47%-63%; I2 = 41%) in 323 patients across 13 studies. Deaths from BSM progression after SRS were rare (19 of 703 [2.7%] deaths across 19 studies), and the neurologic death rate in patients with BSM (24%; 95% CI, 19%-31%; I2 = 62%) was equivalent to the neurologic death rate in patients with BM who were treated on prospective trials. The rate of treatment-related grade 3 to 5 toxic effects was 2.4% (95% CI, 1.5%-3.7%; I2 = 33%) in 1421 patients across 31 studies. These results compared favorably to trials of targeted or immunotherapy for BM, which had a wide objective response rate range from 17% to 56%.

Conclusions And Relevance: Results of this systematic review and meta-analysis show that SRS for BSM was associated with effectiveness and safety and was comparable to SRS for nonbrainstem BM, suggesting that patients with BSM should be eligible for clinical trials of SRS. In this analysis, patients treated with SRS for BSM rarely died from BSM progression and often experienced symptomatic improvement. Given the apparent safety and efficacy of SRS for BSM in the context of acute morbidity or death from BSM growth, consideration of SRS at the time of enrollment on emerging trials of targeted therapy for BM should be considered.
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http://dx.doi.org/10.1001/jamaoncol.2021.1262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120444PMC
July 2021

Effectiveness of Image-Guided Radiotherapy in Adjuvant Radiotherapy on Survival for Localized Breast Cancer: A Population-Based Analysis.

Cancer Manag Res 2021 20;13:3465-3472. Epub 2021 Apr 20.

Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan.

Purpose: Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the radiotherapy delivery. We aimed to compare the overall survival (OS) for localized breast cancer (LBC) patient treated with adjuvant conventional fractionated radiotherapy (CFRT) using IGRT vs those without IGRT via a population-based analysis.

Patients And Methods: Eligible LBC patients diagnosed between 2011 and 2013 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and other outcomes were compared between IGRT and non-IGRT. We also evaluated OS in various supplementary analyses.

Results: Our primary analysis included 6490 patients in whom covariates were well balanced after PS weighing. The HR for death when IGRT was compared with non-IGRT was 1.02 (95% confidence interval 0.80-1.31, P = 0.86). There were also no significant differences in the supplementary analyses.

Conclusion: We found that OS of LBC patients treated with adjuvant CFRT was not statistically different between those treated with IGRT versus without IGRT. This was the first study in this regard to our knowledge but randomized controlled trials were needed to confirm our finding.
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http://dx.doi.org/10.2147/CMAR.S299975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069678PMC
April 2021

Histopathologic findings in malignant peripheral nerve sheath tumor predict response to radiotherapy and overall survival.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa131. Epub 2020 Oct 1.

Department of Radiation Oncology, University of California, San Francisco, California, USA.

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown.

Methods: We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018.

Results: Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) ( = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate ( = .004) in response to radiation.

Conclusions: Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.
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http://dx.doi.org/10.1093/noajnl/vdaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044670PMC
October 2020

Platelet and neutrophil responses to Porphyromonas gingivalis in human whole blood.

Mol Oral Microbiol 2021 06 20;36(3):202-213. Epub 2021 Apr 20.

Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.

Porphyromonas gingivalis is a causative agent for periodontal disease. Binding of platelets to this gram-negative anaerobe can regulate host hemostatic (thrombus forming) and immune (neutrophil interacting) responses during bacterial infection. Additionally, in response to bacterial pathogens neutrophils can release their DNA, forming highly prothrombotic neutrophil extracellular traps (NETs), which then further enhance platelet responses. This study evaluates the role of P. gingivalis on platelet expression of CD62P, platelet-neutrophil interactions, and labeled neutrophil-associated DNA. Human whole blood was preincubated with varying P. gingivalis concentrations, with or without subsequent addition of adenosine diphosphate (ADP). Flow cytometry was employed to measure platelet expression of CD62P using PerCP-anti-CD61 and PE-anti-CD62P, platelet-neutrophil interactions using PerCP-anti-CD61 and FITC-anti-CD16, and the release of neutrophil DNA using FITC-anti-CD16 and Sytox Blue labeling. Preincubation with a high (6.25 × 10  CFU/mL) level of P. gingivalis significantly increased platelet expression of CD62P in ADP treated and untreated whole blood. In addition, platelet-neutrophil interactions were significantly increased after ADP stimulation, following 5-22 min preincubation of blood with high P. gingivalis CFU. However, in the absence of added ADP, platelet-neutrophil interactions increased in a manner dependent on the preincubation time with P. gingivalis. Moreover, after ADP addition, 16 min preincubation of whole blood with P. gingivalis led to increased labeling of neutrophil-associated DNA. Taken together, the results suggest that the presence of P. gingivalis alters platelet and neutrophil responses to increase platelet activation, platelet interactions with neutrophils, and the level of neutrophil antimicrobial NETs.
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http://dx.doi.org/10.1111/omi.12336DOI Listing
June 2021

Immunogenic Cell Death by the Novel Topoisomerase I Inhibitor TLC388 Enhances the Therapeutic Efficacy of Radiotherapy.

Cancers (Basel) 2021 Mar 11;13(6). Epub 2021 Mar 11.

Cancer Center, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.

Rectal cancer accounts for 30-40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30-40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.
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http://dx.doi.org/10.3390/cancers13061218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998596PMC
March 2021

Polymorphism of formyl peptide receptor 1 (FPR1) reduces the therapeutic efficiency and antitumor immunity after neoadjuvant chemoradiotherapy (CCRT) treatment in locally advanced rectal cancer.

Cancer Immunol Immunother 2021 Mar 13. Epub 2021 Mar 13.

Cancer Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan-Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374-10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes.
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http://dx.doi.org/10.1007/s00262-021-02894-8DOI Listing
March 2021

Noninferiority clinical trial comparing the bowel cleansing efficacy of sodium phosphate tablets (Quiklean) with a polyethylene glycol/bisacodyl kit.

World J Gastroenterol 2021 Feb;27(5):428-441

Department of Colorectal Surgery, China Medical University Hsinchu Hospital, Zhubei 30272, Taiwan.

Background: Efficient bowel cleansing is essential for a successful colonoscopy, but the ideal cleansing agent, volume, and pharmaceutical dosage form have yet to be determined. Small-volume cleansers enhance patient compliance.

Aim: To compare the bowel cleansing efficacy of 32-tablet sodium phosphate (Quiklean) with 2-L polyethylene glycol (PEG)/bisacodyl (Klean-Prep/ Dulcolax) under identical dietary recommendations.

Methods: This multicenter, randomized, parallel-group, noninferiority clinical trial enrolled 472 outpatients, randomized 456 subjects, and scheduled 442 subjects to undergo colonoscopy (Quiklean = 222 and Klean-Prep/Dulcolax = 220). After bowel preparation, a colonoscopist performed the colonoscopy with video recorded for rating. The primary efficacy endpoint was the bowel cleansing quality using the Aronchick Scale. The secondary endpoints were the bowel cleansing efficacy of three colon segments, tolerability and acceptability, safety using the Ottawa bowel preparation scale, questionnaires by subjects, and monitoring of adverse events.

Results: Success rates (Excellent + Good) of the bowel cleansing quality by Aronchick Scale were 98.6% ( = 205) and 97.6% ( = 204) in the Quiklean and Klean-Prep/Dulcolax groups, respectively. Quiklean demonstrated noninferiority over Klean-Prep/Dulcolax in colon cleansing efficacy. Quicken showed better tolerability and acceptability in the overall experience (was rated as excellent; 24.0% 17.2%; = 0.0016) and the taste of the study preparation (was rated as excellent, 23.1% 13.4%; < 0.0001) than Klean-Prep/Dulcolax. Safety profiles did not differ between the two groups. Our data indicate that Quiklean is an adequate, well-tolerated bowel cleansing preparation compared with the standard comparator Klean-Prep/Dulcolax.

Conclusion: Quiklean is sodium phosphate tablets available on Taiwan's market for bowel preparation; it potentially offers patients an alternative to standard large-volume bowel preparation regimens and may, therefore, increase positive attitudes toward colonoscopies and participation rates.
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http://dx.doi.org/10.3748/wjg.v27.i5.428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856840PMC
February 2021

ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.

J Cell Physiol 2021 Sep 12;236(9):6481-6495. Epub 2021 Feb 12.

Cancer Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.

AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45 intratumoral infiltrating lymphocytes (TILs) and memory CD45RO TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.
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http://dx.doi.org/10.1002/jcp.30323DOI Listing
September 2021

Transplantation of Purified Human Pericytes for Myocardial Repair in SCID-hu Mice.

Methods Mol Biol 2021 ;2235:13-26

Research Laboratory of Electronics and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

The physiological, pathological, and regenerative roles of pericytes as microvascular mural cells and multipotent precursors have gained significant attention. The capacity to prospectively purify pericytes from multiple organs enables the investigation of their tissue-specific regenerative capabilities. Here, we describe the application of purified human pericytes for cardiac regeneration post-infarct in an immunodeficient mouse model. This protocol includes experimental details of pericyte isolation from both human skeletal and cardiac muscle, an immunodeficient mouse model of acute myocardial infarction, and xenogeneic pericyte transplantation.
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http://dx.doi.org/10.1007/978-1-0716-1056-5_2DOI Listing
March 2021

Natural orifice versus conventional mini-laparotomy for specimen extraction after reduced-port laparoscopic surgery for colorectal cancer: propensity score-matched comparative study.

Surg Endosc 2021 Feb 2. Epub 2021 Feb 2.

Division of Colorectal Surgery, Department of Surgery, China Medical University Hospital, China Medical University, No. 2, Yu-Der Rd, Taichung, 404, Taiwan.

Background: Although reduced port laparoscopic surgery (RPLS), defined as laparoscopic surgery performed with the minimum possible number of ports and/or small-sized ports, is less invasive than conventional laparoscopic surgery by reducing the number of surgical wounds, an extension of the incision is still needed for specimen extraction, which can undermine the merits of RPLS.

Objective: To determine the impact of natural orifice specimen extraction (NOSE) in patients undergoing RPLS for colorectal cancer. The endpoints were perioperative outcome and oncologic safety at 3 years.

Setting: Single-center experience (2013-2019).

Patients: We retrospectively analyzed our prospectively collected patient records (American Joint Committee on Cancer (AJCC) stage I-III sigmoid or upper rectal cancer (tumor diameter ≤ 5 cm) who underwent curative anterior resection via RPLS. We excluded patients who did not undergo intestinal anastomosis.

Interventions: Perioperative and oncologic outcomes were compared between patients undergoing natural orifice (RPLS-NOSE) or conventional (mini-laparotomy) specimen extraction (RPLS-CSE). Patients were matched by propensity scores 1:1 for tumor diameter, AJCC stage, American Society of Anesthesiologists score and tumor location.

Results: Of 119 eligible patients, 104 were matched (52 RPLS-NOSE; 52 RPLS-CSE) by propensity scores. Compared with RPLS-CSE, RPLS-NOSE was associated with longer operative time (223.9 vs. 188.7 min; p = 0.003), decreased use of analgesics (morphine dose 33.9 vs. 43.4 mg; p = 0.011) and duration of hospital stay (4.2 vs. 5.1 days; p = 0.001). No statistically significant difference was found in morbidity or wound-related complication rates between the two groups. After a median follow-up of 34.3 months, no local recurrence was observed in RPLS-NOSE. The 3-year disease-free survival did not differ statistically significantly between groups (90.9 vs. 90.5%; p = 0.610).

Conclusion: NOSE enhances the advantages of RPLS by avoiding the need for abdominal wall specimen extraction in patients with tumor diameter ≤ 5 cm. Surgical and oncologic safety are comparable to RPLS with CSE.
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http://dx.doi.org/10.1007/s00464-020-08250-8DOI Listing
February 2021

Impact of the COVID-19 Pandemic Surge on Radiation Treatment: Report From a Multicenter New York Area Institution.

JCO Oncol Pract 2021 Feb 2:OP2000619. Epub 2021 Feb 2.

Academic Department of Radiation Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.

Purpose: During the COVID-19 surge months of March and April 2020, our New York multicenter health system experienced an influx of cases with COVID-19. We sought to study the impact of the surge period on patients with cancer prescribed radiation treatment (RT).

Methods: We reviewed our secure departmental quality assurance database for all patients who underwent RT planning simulations from March 6, 2020, through April 30, 2020. A priority level between 1 and 3 was prospectively assigned to each case based on faculty consensus to determine which patients required immediate RT. In May 2020, each faculty physician again retrospectively reviewed their patients from the database and provided additional commentary on how the COVID-19 pandemic had affected each patient's care. All statistics are descriptive.

Results: A total of 412 RT courses in 406 unique patients were simulated for linear accelerator-based external beam RT. The median age was 66 years. Treatment intent was curative in 70.6% and palliative in 29.4%. Of the 412 cases, 66.7% were priority 1, 25% priority 2, and 7.8% priority 3. Two hundred thirty-nine cases (58%) underwent standard-of-care diagnosis, workup, and treatment plan. Seventeen patients (4.1%) electively canceled their RT, and 17 others (4.1%) electively delayed RT start. Thirty-four (8.3%) were prescribed hypofractionation to shorten their RT course, and 22 (5.3%) had a change in modality. Incomplete or delayed workup was identified in 19 cases (4.6%).

Conclusion: The COVID-19 pandemic surge resulted in 42% of our patients having a non-standard-of-care pathway. This outcome demonstrates a significant impact of the COVID-19 crisis on routine cancer care.
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http://dx.doi.org/10.1200/OP.20.00619DOI Listing
February 2021

Image-Guided Percutaneous Ablation of Adrenal Metastases: A Meta-Analysis of Efficacy and Safety.

J Vasc Interv Radiol 2021 04 29;32(4):527-535.e1. Epub 2021 Jan 29.

Department of Radiology & Biomedical Imaging, University of California, San Francisco, California; Department of Urology, University of California, San Francisco, California.

Purpose: To evaluate the efficacy and safety of percutaneous ablation of adrenal metastases through a meta-analysis of various image-guided percutaneous ablation techniques.

Materials And Methods: A comprehensive literature search of PubMed and Embase databases was performed for studies evaluating the efficacy and/or safety of image-guided percutaneous ablation of adrenal metastases. A total of 37 studies published between 2009 and 2020 were analyzed, comprising a sample size of 959 patients. Proportion estimates of overall survival, local control, and toxicity were analyzed in a pooled meta-analysis. The pooled prevalence of adverse events after ablation was calculated based on common terminology criteria for adverse events (CTCAE) grading.

Results: Of the 959 included patients, 320 (33.3%) underwent radiofrequency ablation, 72 (7.5%) microwave ablation, 95 (9.9%) cryoablation, and 46 (4.8%) ethanol injections for treatment of adrenal metastases. The remaining 426 (44.4%) patients were from studies involving a mixture of the 4 listed percutaneous ablation techniques. The pooled 1-year local control rate was 80% (95% confidence interval [CI], 76%-83%). The pooled 1-year overall survival rate was 77% (95% CI, 70%-83%). The overall rate of severe adverse events after ablation (CTCAE grade 3 or higher) was 16.1%. The overall rate of low-grade adverse events after ablation (CTCAE grade 2 or lower) was 32.6%. Approximately 21.9% (n = 203) of patients experienced intraprocedural hypertensive crises, the majority of which were reversed with antihypertensive medications.

Conclusions: This study demonstrates that image-guided percutaneous ablation can be effective in achieving acceptable short- to mid-term local tumor control and overall survival with a moderate safety profile.
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http://dx.doi.org/10.1016/j.jvir.2020.12.010DOI Listing
April 2021

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

The Manchester Respiratory Activities of Daily Living Questionnaire: Reliability and Validity of the Chinese Version with Pictorial Enhancement.

Int J Chron Obstruct Pulmon Dis 2021;16:91-100. Epub 2021 Jan 15.

Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong SAR.

Background: The Manchester Respiratory Activities of Daily Living Questionnaire (MRADLQ) is a valid and reliable tool measuring the functional level of patients with COPD in multidimensional aspects. However, a local validation of the questionnaire is lacking in Hong Kong.

Objective: To develop a Chinese version of MRADLQ with pictorial enhancement (C-MRADLQ) and study its reliability and validity.

Patients And Methods: A total of 238 patients suffering from COPD were recruited from nine public hospitals and five Nurse and Allied Health Respiratory Clinics by convenient sampling. A total of 64 patients with normal spirometry results and no previous clinical diagnosis of COPD were invited to complete the C-MRADLQ for comparison and examination of its validity. Ten out of 302 patients were re-assessed with the C-MRADLQ after one week by the same rater for test-retest reliability. The C-MRADLQ was correlated with spirometry result, COPD classifications and groups by Global Initiative for Chronic Obstructive Lung Disease (GOLD), the modified Medical Research Council Dyspnea Scale (mMRC Dyspnea Scale), COPD Assessment Test (CAT), Chinese Version of the Shortness of Breath Questionnaire (C-SOBQ), number of admission and the ADO index.

Results: The C-MRADLQ shows good test-retest reliability as indicated by an intra-class correlation coefficient value of 0.975. It is significantly correlated with COPD stage, COPD group, SOBQ score, CAT score, mMRC, ADO index, spirometry results, and number of admissions. The SOBQ score, number of admissions, FEV1/FVC, and COPD group could significantly predict the total C-MRADLQ score. A total of 67.9% of participants' mMRC levels were correctly classified by using the C-MRADLQ total score. The agreement of the original and new versions of questions 20 and 21 of C-MRADLQ was 97.3% and 90.1%, respectively.

Conclusion: The pictorial version of the C-MRADLQ is a validated and reliable functional assessment tool to measure functional status among patients with COPD in the Chinese population.
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http://dx.doi.org/10.2147/COPD.S283769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816045PMC
June 2021

Stereotactic Body Radiation Therapy and High-Dose-Rate Brachytherapy Boost in Combination With Intensity Modulated Radiation Therapy for Localized Prostate Cancer: A Single-Institution Propensity Score Matched Analysis.

Int J Radiat Oncol Biol Phys 2021 Jun 30;110(2):429-437. Epub 2020 Dec 30.

Department of Radiation Oncology, University of California San Francisco, San Francisco, California. Electronic address:

Purpose: To perform a propensity-score matched analysis comparing stereotactic body radiation therapy (SBRT) boost and high-dose-rate (HDR) boost for localized prostate cancer.

Methods And Materials: A single-institution retrospective chart review was conducted of men treated with pelvic external beam radiation therapy (EBRT) and SBRT boost (21 Gy and 19 Gy in 2 fractions) to the prostate for prostate cancer. A cohort treated at the same institution with HDR brachytherapy boost (19 Gy in 2 fractions) was compared. Propensity-score (PS) matching and multivariable Cox regression were used for analysis. Outcomes were biochemical recurrence freedom (BCRF) and metastasis freedom (MF).

Results: One hundred thirty-one men were treated with SBRT boost and 101 with HDR boost with median follow-up of 73.4 and 186.0 months, respectively. In addition, 68.8% of men had high-risk and 26.0% had unfavorable-intermediate disease, and 94.3% received androgen deprivation therapy. Five- and 10-year unadjusted BCRF was 88.8% and 85.3% for SBRT and 91.8% and 74.6% for HDR boost (log-rank P = .3), and 5- and 10-year unadjusted MF was 91.7% and 84.3% for SBRT and 95.8% and 82.0% for HDR (log-rank P = .8). After adjusting for covariates, there was no statistically significant difference in BCRF (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.37-1.79; P = .6) or MF (HR 1.07; 95% CI, 0.44-2.57; P = .9) between SBRT and HDR boost. Similarly, after PS matching, there was no statistically significant difference between SBRT and HDR (BCRF: HR 0.66, 0.27-1.62, P = .4; MF: HR 0.84, 0.31-2.26, P = .7). Grade 3+ genitourinary and gastrointestinal toxicity in the SBRT cohort were 4.6% and 1.5%, and 3.0% and 0.0% in the HDR cohorts (P = .4, Fisher exact test).

Conclusions: SBRT boost plus pelvic EBRT for prostate cancer resulted in similar BCRF and MF to HDR boost in this single institution, PS matched retrospective analysis. Toxicity was modest. Prospective evaluation of SBRT boost for the treatment of unfavorable-intermediate and high-risk prostate cancer is warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.034DOI Listing
June 2021

Laparoscopic retrojejunal trans-mesenteric anastomosis for extended left-sided colorectal resections - a new solution to an old problem.

Colorectal Dis 2021 May 11;23(5):1262-1267. Epub 2021 Jan 11.

Division of Colorectal Surgery, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.

Aim: Following extended left-sided colorectal resection, creation of the anastomosis can be challenging due to insufficient length of the remaining proximal and distal bowel. Retroileal pull-through and the Deloyers procedure are feasible but require ligation of the middle colic vessels and additional right colonic mobilization. The aim of this study was to describe our initial experience with an alternative technique for performing tension-free anastomosis following minimally invasive left-sided resection.

Method: This was a retrospective case series of all patients who underwent a retrojejunal trans-mesenteric pull-through following elective laparoscopic left-sided colorectal surgery between September 2019 and September 2020. Placing the retrojejunal window 15-20 cm distal to the duodenojejunal junction allows the transverse colon to pass via the most direct route through the base of the proximal jejunal mesentery to the distal colon or rectal stump instead of passing over the small bowel, yielding additional length for the anastomosis. An accompanying video demonstrates this technique for three different case scenarios.

Results: Seven consecutive patients underwent this approach following colorectal resection; three had inherently shorter left colons, two had synchronous left-sided tumours and two had inadvertent intraoperative marginal artery injury. There were no anastomotic complications or early postoperative morbidity related to the mesenteric window. The additional time taken for the procedure ranged from 5 to 35 min. The risk of complications related to extended left-sided resections may possibly be reduced, although further studies are required to evaluate this.

Conclusion: Retrojejunal trans-mesenteric pull-through is a novel, but straightforward, safe and useful option for reducing tension in laparoscopic left-sided colorectal anastomoses.
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http://dx.doi.org/10.1111/codi.15501DOI Listing
May 2021

Prognostic relevance of programmed cell death 1 ligand 2 (PDCD1LG2/PD-L2) in patients with advanced stage colon carcinoma treated with chemotherapy.

Sci Rep 2020 12 18;10(1):22330. Epub 2020 Dec 18.

Cancer Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8 tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p < 0.001), especially in advanced stage colon carcinoma patients. Low tumor PD-L2 expression was associated with an increased 5-year OS risk among advanced stage colon carcinoma patients by univariate analysis [hazard ratio (HR) = 1.69, 95% CI 1.324-2.161, p < 0.001] and multivariate analysis [HR = 1.594, 95% CI 1.206-2.106, p = 0.001]. Moreover, tumor PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, suggesting that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity. Taken together, these results show that tumor PD-L2 expression may be an independent prognostic factor for survival outcome in patients with advanced stage colon carcinoma.
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http://dx.doi.org/10.1038/s41598-020-79419-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749140PMC
December 2020

The Eyelid Crease Height, Depth, and Shape: A Scoring System for Revisional Asian Blepharoplasty.

Plast Reconstr Surg Glob Open 2020 May 29;8(5):e2802. Epub 2020 May 29.

Jules Stein Eye Institute, Department of Ophthalmology, UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance, Calif.

This study reports on a series of challenging revisional Asian blepharoplasty cases with various suboptimal factors, including high or low crease height, shallow or deep crease indentation (depth), and suboptimal crease shape. The study also presents a simple scoring scale that combines these challenges into a composite score, which has helped in the management of these cases.

Methods: Data on 64 revisional cases were collected between January 1, 2006, and June 30, 2019, with 126 upper eyelids. These were cases with little skin remaining after previous surgeries, and each eyelid was scored based on a . A composite score (H + D + S) is then summed up, which ranged from 1 to 10, with the higher number being the most challenging. The logic and rules behind this scoring scale are explained.

Results: Data regarding age, gender, and eyelid crease characteristics of the cases were collected; photographs, notes, and diagrams in the medical records were used to complete each eyelid's scoring. The age of the patients (57 women and 7 men) ranged from 21 to 74 years. The revision score distribution, age distribution, and averaged scores within each age group were investigated for those starting at 24 years or younger, and for each added decade until over 65 years. Patients with revisional effort scores of 5-8 were found in all age groups surveyed.

Conclusions: In this study, the author presents a practical scoring scale that recognizes the factors responsible for the suboptimal results in double eyelid plasty and helps clinicians in management, patient-counseling, and planning of surgical solutions.
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http://dx.doi.org/10.1097/GOX.0000000000002802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605888PMC
May 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

bioRxiv 2020 Oct 29. Epub 2020 Oct 29.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
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http://dx.doi.org/10.1101/2020.10.28.359935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605559PMC
October 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

Res Sq 2020 Oct 28. Epub 2020 Oct 28.

Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, CA 94143-0511, USA.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
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http://dx.doi.org/10.21203/rs.3.rs-97042/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605560PMC
October 2020

Autoantibody Landscape in Patients with Advanced Prostate Cancer.

Clin Cancer Res 2020 12 23;26(23):6204-6214. Epub 2020 Sep 23.

Serimmune, Inc. Santa Barbara, California.

Purpose: Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC).

Experimental Design: Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes.

Results: SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1.

Conclusions: We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710628PMC
December 2020

Platelet plug formation in whole blood is enhanced in the presence of Porphyromonas gingivalis.

Mol Oral Microbiol 2020 12 10;35(6):251-259. Epub 2020 Oct 10.

Division of Biochemistry, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.

Porphyromonas gingivalis is a gram-negative anaerobic bacterium and an etiologic agent of adult periodontitis. By inducing a dysbiotic state within the host microbiota it contributes to a chronic inflammatory environment in the oral cavity. Under some circumstances, the oral bacteria may gain access to systemic circulation. While the most widely recognized function of platelets is to reduce hemorrhage in case of vascular damage, it is known that platelets are also involved in the hematologic responses to bacterial infections. Some pathogenic bacteria can interact with platelets, triggering their activation and aggregation. The aim of this study was to assess platelet responses to the presence of P. gingivalis in whole blood. Human whole blood was pretreated with P. gingivalis and then platelet plug formation was measured under high shear conditions using the PFA-100. In the presence of P. gingivalis, time for a platelet plug to occlude the aperture in the collagen/ADP cartridge was shortened in a manner dependent on bacterial concentration and the duration of bacterial preincubation of blood. P. gingivalis enhances thrombus forming potential of platelets in whole blood.
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http://dx.doi.org/10.1111/omi.12314DOI Listing
December 2020
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