Publications by authors named "Andrew Wang"

803 Publications

Predicting patient-specific response to adaptive therapy in metastatic castration-resistant prostate cancer using prostate-specific antigen dynamics.

Neoplasia 2021 Jul 20;23(9):851-858. Epub 2021 Jul 20.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.
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http://dx.doi.org/10.1016/j.neo.2021.06.013DOI Listing
July 2021

Asymmetric multi-task attention network for prostate bed segmentation in computed tomography images.

Med Image Anal 2021 Aug 28;72:102116. Epub 2021 May 28.

Department of Radiation Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Post-prostatectomy radiotherapy requires accurate annotation of the prostate bed (PB), i.e., the residual tissue after the operative removal of the prostate gland, to minimize side effects on surrounding organs-at-risk (OARs). However, PB segmentation in computed tomography (CT) images is a challenging task, even for experienced physicians. This is because PB is almost a "virtual" target with non-contrast boundaries and highly variable shapes depending on neighboring OARs. In this work, we propose an asymmetric multi-task attention network (AMTA-Net) for the concurrent segmentation of PB and surrounding OARs. Our AMTA-Net mimics experts in delineating the non-contrast PB by explicitly leveraging its critical dependency on the neighboring OARs (i.e., the bladder and rectum), which are relatively easy to distinguish in CT images. Specifically, we first adopt a U-Net as the backbone network for the low-level (or prerequisite) task of the OAR segmentation. Then, we build an attention sub-network upon the backbone U-Net with a series of cascaded attention modules, which can hierarchically transfer the OAR features and adaptively learn discriminative representations for the high-level (or primary) task of the PB segmentation. We comprehensively evaluate the proposed AMTA-Net on a clinical dataset composed of 186 CT images. According to the experimental results, our AMTA-Net significantly outperforms current clinical state-of-the-arts (i.e., atlas-based segmentation methods), indicating the value of our method in reducing time and labor in the clinical workflow. Our AMTA-Net also presents better performance than the technical state-of-the-arts (i.e., the deep learning-based segmentation methods), especially for the most indistinguishable and clinically critical part of the PB boundaries. Source code is released at https://github.com/superxuang/amta-net.
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http://dx.doi.org/10.1016/j.media.2021.102116DOI Listing
August 2021

NF-κB responds to absolute differences in cytokine concentrations.

Sci Signal 2021 Jan;14(666)

Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.

Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure such dynamic inputs is not well understood. Here, we used microfluidic single-cell analysis and mathematical modeling to study how the NF-κB pathway responds to immune inputs that vary over time such as increasing, decreasing, or fluctuating cytokine signals. We found that NF-κB activity responded to the absolute difference in cytokine concentration and not to the concentration itself. Our analyses revealed that negative feedback by the regulatory proteins A20 and IκBα enabled differential responses to changes in cytokine dose by providing a short-term memory of previous cytokine concentrations and by continuously resetting kinase cycling and receptor abundance. Investigation of NF-κB target gene expression showed that cells exhibited distinct transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244746PMC
January 2021

Asymmetrical Multi-task Attention U-Net for the Segmentation of Prostate Bed in CT Image.

Med Image Comput Comput Assist Interv 2020 Oct 29;12264:470-479. Epub 2020 Sep 29.

Department of Radiology and BRIC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Segmentation of the prostate bed, the residual tissue after the removal of the prostate gland, is an essential prerequisite for post-prostatectomy radiotherapy but also a challenging task due to its non-contrast boundaries and highly variable shapes relying on neighboring organs. In this work, we propose a novel deep learning-based method to automatically segment this "invisible target". As the main idea of our design, we expect to get reference from the surrounding normal structures (bladder&rectum) and take advantage of this information to facilitate the prostate bed segmentation. To achieve this goal, we first use a U-Net as the backbone network to perform the bladder&rectum segmentation, which serves as a low-level task that can provide references to the high-level task of the prostate bed segmentation. Based on the backbone network, we build a novel attention network with a series of cascaded attention modules to further extract discriminative features for the high-level prostate bed segmentation task. Since the attention network has one-sided dependency on the backbone network, simulating the clinical workflow to use normal structures to guide the segmentation of radiotherapy target, we name the final composition model asymmetrical multi-task attention U-Net. Extensive experiments on a clinical dataset consisting of 186 CT images demonstrate the effectiveness of this new design and the superior performance of the model in comparison to the conventional atlas-based methods for prostate bed segmentation. The source code is publicly available at https://github.com/superxuang/amta-net.
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http://dx.doi.org/10.1007/978-3-030-59719-1_46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221064PMC
October 2020

Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.

Elife 2021 06 21;10. Epub 2021 Jun 21.

Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.

Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.
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http://dx.doi.org/10.7554/eLife.66522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245129PMC
June 2021

THE ASSOCIATION BETWEEN COMPLEX CATARACT SURGERY AND SOCIAL DETERMINANTS OF HEALTH IN FLORIDA.

Ophthalmic Epidemiol 2021 Jun 17:1-7. Epub 2021 Jun 17.

Department of Ophthalmology and Center for Health Services and Outcomes Research, Northwestern University, Chicago, Illinois, USA.

: To analyze differences between rates of complex and routine cataract surgery based on demographics and social determinants of health (SDOH) at the community level.: Data from adults ages 18 to 84 relevant to cataract surgery billing codes were extracted from the 2017 Florida Ambulatory Surgery dataset from the Agency for Healthcare Research and Quality merged with SDOH measures from the American Community Survey. A multivariable logistic regression model was used to determine associations between complex cataract surgery and SDOH according to patient ZIP code. Outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI).: A total of 171,754 and 11,340 patients received routine and complex cataract surgeries, respectively; females received the majority of routine surgeries (58.87%); most common age group (79.11%) was from 65 to 84 years. Male (odds ratio [OR] 2.034; < 0.0001) and black patients (OR 1.998; < 0.0001) more likely received complex surgery. Compared to Medicare patients, patients insured with Medicaid (OR 2.058; < 0.0001), private insurance (OR 1.057; = 0.0182), or self-pay (OR 1.570; < 0.0001) were more likely to receive a complex surgery. ZIP codes with higher adult poverty (OR 2.614; < 0.001) were more likely complex surgery patients, whereas those with higher rates of high school attendance (OR 0.487; = 0.0193) and home occupancy (OR 0.704; = 0.0047) were less likely to be complex.: Selected patient- and community-level factors including being male, Black, Asian, Hispanic, non-Medicare, or within lower education, higher poverty ZIP codes were associated with a higher likelihood of receiving complex cataract surgery.
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http://dx.doi.org/10.1080/09286586.2021.1939888DOI Listing
June 2021

Sensitive detection and quantification of SARS-CoV-2 in saliva.

Sci Rep 2021 06 14;11(1):12425. Epub 2021 Jun 14.

Section of Hematology and Oncology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.

Saliva has significant advantages as a test medium for detection of SARS-CoV-2 infection in patients, such as ease of collection, minimal requirement of supplies and trained personnel, and safety. Comprehensive validation in a large cohort of prospectively collected specimens with unknown SARS-CoV-2 status should be performed to evaluate the potential and limitations of saliva-based testing. We developed a saliva-based testing pipeline for detection of SARS-CoV-2 nucleic acids using real-time reverse transcription PCR (RT-PCR) and droplet digital PCR (ddPCR) readouts, and measured samples from 137 outpatients tested at a curbside testing facility and 29 inpatients hospitalized for COVID-19. These measurements were compared to the nasal swab results for each patient performed by a certified microbiology laboratory. We found that our saliva testing positively detects 100% (RT-PCR) and 93.75% (ddPCR) of curbside patients that were identified as SARS-CoV-2 positive by the Emergency Use Authorization (EUA) certified nasal swab testing assay. Quantification of viral loads by ddPCR revealed an extremely wide range, with 1 million-fold difference between individual patients. Our results demonstrate for both community screening and hospital settings that saliva testing reliability is on par with that of the nasal swabs in detecting infected cases, and has potential for higher sensitivity when combined with ddPCR in detecting low-abundance viral loads that evade traditional testing methods.
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http://dx.doi.org/10.1038/s41598-021-91835-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203799PMC
June 2021

Clinical predictors of poor 30-day headache outcomes after an emergency department visit for acute post-traumatic headache.

Am J Emerg Med 2021 Jun 9;49:158-162. Epub 2021 Jun 9.

Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, 111 East 210th Street, Bronx, NY 10467, USA. Electronic address:

Purpose: We investigated clinical risk factors that predict poor 30-day headache outcomes among patients evaluated in the emergency department (ED) for post-traumatic headache (PTH).

Methods: This was an analysis of data from a randomized, placebo-controlled study of IV metoclopramide + diphenhydramine for acute PTH. Patients were enrolled during an ED visit and received telephone follow-up with a structured questionnaire 30 days later. The primary outcome was frequency of headaches 30 days after ED discharge. We used multivariable logistic regression models to determine which clinical variables were associated with frequent headaches at 30 days.

Results: In total, 160 patients were enrolled in the study. 134 (84%) patients completed the 30-day questionnaire and were included in the analysis, including 90 females and 44 males. 30 patients (22%, 95% CI = 0.16 to 0.30) reported frequent headaches at 30-day follow-up. In the multivariable analysis, female sex (OR = 4.03, 95% CI = 1.23±13.13), patients who blamed themselves for their injury (OR = 0.13, 95% CI = 0.04±0.45), and patients who were unsure if they sustained loss of consciousness during the traumatic incident (OR = 5.63, 95% CI = 1.89±16.78) were found to be associated with poor 30-day outcomes. Medication received in the ED and age were not associated.

Conclusions: More than 1 out of five patients treated in the ED for acute PTH experienced frequent headaches 30 days later. Women and patients who were uncertain as to whether they had experienced loss of consciousness were at increased risk of frequent PTH. Blaming oneself for the head trauma was associated with less frequent PTH.
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http://dx.doi.org/10.1016/j.ajem.2021.05.075DOI Listing
June 2021

Endoscopic Ultrasound-guided Fine-needle Biopsy With or Without Rapid On-site Evaluation for Diagnosis of Solid Pancreatic Lesions: A Randomized Controlled Non-Inferiority Trial.

Gastroenterology 2021 Jun 9. Epub 2021 Jun 9.

Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.

Background And Aims: The benefit of rapid on-site evaluation (ROSE) on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has never been evaluated in a randomized study. This trial aimed to test the hypothesis that in solid pancreatic lesions (SPLs), diagnostic accuracy of EUS-FNB without ROSE was not inferior to that of EUS-FNB with ROSE.

Methods: A noninferiority study (noninferiority margin, 5%) was conducted at 14 centers in 8 countries. Patients with SPLs requiring tissue sampling were randomly assigned (1:1) to undergo EUS-FNB with or without ROSE using new-generation FNB needles. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy, and secondary endpoints were safety, tissue core procurement, specimen quality, and sampling procedural time.

Results: Eight hundred patients were randomized over an 18-month period, and 771 were analyzed (385 with ROSE and 386 without). Comparable diagnostic accuracies were obtained in both arms (96.4% with ROSE and 97.4% without ROSE, P = .396). Noninferiority of EUS-FNB without ROSE was confirmed with an absolute risk difference of 1.0% (1-sided 90% confidence interval, -1.1% to 3.1%; < .001). Safety and sample quality of histologic specimens were similar in both groups. A significantly higher tissue core rate was obtained by EUS-FNB without ROSE (70.7% vs. 78.0%, P = .021), with a significantly shorter mean sampling procedural time (17.9 ± 8.8 vs 11.7 ± 6.0 minutes, P < .0001).

Conclusions: EUS-FNB demonstrated high diagnostic accuracy in evaluating SPLs independently on execution of ROSE. When new-generation FNB needles are used, ROSE should not be routinely recommended. (ClinicalTrial.gov number NCT03322592.).
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http://dx.doi.org/10.1053/j.gastro.2021.06.005DOI Listing
June 2021

Predicting thermal pleasure experienced in dynamic environments from simulated cutaneous thermoreceptor activity.

Indoor Air 2021 May 28. Epub 2021 May 28.

Center for the Built Environment (CBE), University of California Berkeley, Berkeley, California, USA.

Research into human thermal perception indoors has focused on "neutrality" under steady-state conditions. Recent interest in thermal alliesthesia has highlighted the hedonic dimension of our thermal world that has been largely overlooked by science. Here, we show the activity of sensory neurons can predict thermal pleasure under dynamic exposures. A numerical model of cutaneous thermoreceptors was applied to skin temperature measurements from 12 human subjects. A random forest model trained on simulated thermoreceptor impulses could classify pleasure responses (F1 score of 67%) with low false positives/negatives (4%). Accuracy increased (83%) when excluding the few extreme (dis)pleasure responses. Validation on an independent dataset confirmed model reliability. This is the first empirical demonstration of the relationship between thermoreceptors and pleasure arising from thermal stimuli. Insights into the neurophysiology of thermal perception can enhance the experience of built environments through designs that promote sensory excitation instead of neutrality.
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http://dx.doi.org/10.1111/ina.12859DOI Listing
May 2021

The effect of intravenous ketamine on cognitive functions in adults with treatment-resistant major depressive or bipolar disorders: Results from the Canadian rapid treatment center of excellence (CRTCE).

Psychiatry Res 2021 Aug 13;302:113993. Epub 2021 May 13.

Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Mood Disorders Psychopharmacology Unit, Poul Hansen Depression Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Ketamine may exert pro-cognitive effects on select measures of cognition in adults with mood disorders. We evaluated the effectiveness of intravenous (IV) ketamine on cognition in 68 adult outpatients with treatment-resistant depression (TRD) at the Canadian Rapid Treatment Center of Excellence between July 3, 2018 and April 16, 2020 (NCT04209296). Eligibility criteria for the present retrospective study included: primary diagnosis of major depressive or bipolar disorder; currently depressed; and insufficient response to two or more prior treatments. Participants received four infusions of ketamine hydrochloride (0.5-0.75 mg/kg) over 1-2 weeks. We assessed objective and subjective measures of cognition before and after two infusions, i.e., Digit Symbol Substitution Test (DSST), Trail Making Test-B (TMT-B), Patient Deficits Questionnaire, 5-item (PDQ-5-D). Ketamine significantly improved DSST (effect size [ES]=0.60), TMT-B (ES=0.84), as well as PDQ-5-D scores (ES=0.63), indicative of a moderate-to-large effect size. Improvements in DSST and PDQ-5-D with ketamine were mediated by reductions in depressive symptoms, whereas improvements in TMT-B were independent of changes in depressive symptoms. Our results support the independent, rapid-onset, pro-cognitive effects with IV ketamine in adults with TRD. Larger, randomized, controlled trials with ketamine wherein cognition is the primary outcome measure in mood and non-mood disorder samples are warranted.
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http://dx.doi.org/10.1016/j.psychres.2021.113993DOI Listing
August 2021

Diversity and inclusion in neurosurgery.

Lancet Neurol 2021 06;20(6):419-420

David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

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http://dx.doi.org/10.1016/S1474-4422(21)00111-3DOI Listing
June 2021

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

J Hepatol 2021 May 13. Epub 2021 May 13.

Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

Background And Aims: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19.

Methods: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.

Results: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.

Conclusion: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients.

Lay Summary: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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http://dx.doi.org/10.1016/j.jhep.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285256PMC
May 2021

Immune Checkpoint-Bioengineered Beta Cell Vaccine Reverses Early-Onset Type 1 Diabetes.

Adv Mater 2021 Jun 8;33(25):e2101253. Epub 2021 May 8.

Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that results from autoreactive T cells destroying insulin-producing pancreatic beta (β) cells. The development of T1DM is associated with the deficiency of co-inhibitory immune checkpoint ligands (e.g., PD-L1, CD86, and Gal-9) in β cells. Here, a new translational approach based on metabolic glycoengineering and bioorthogonal click chemistry, which bioengineers β cells with co-inhibitory immune checkpoint molecules that induce antigen-specific immunotolerance and reverse early-onset hyperglycemia is reported. To achieve this goal, a subcutaneous injectable acellular pancreatic extracellular matrix platform for localizing the bioengineered β cells while creating a pancreas-like immunogenic microenvironment, in which the autoreactive T cells can interface with the β cells, is devised.
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http://dx.doi.org/10.1002/adma.202101253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222180PMC
June 2021

Development of an automated ERCP Quality Report Card using structured data fields.

Tech Innov Gastrointest Endosc 2021 18;23(2):129-138. Epub 2021 Jan 18.

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA.

Background And Aims: Measuring adherence to ERCP quality indicators (QIs) is confounded by variability in indications, maneuvers, and documentation styles. We hypothesized that incorporation of mandatory, structured data fields within reporting software would permit accurate measurement of QI adherence rates and facilitate generation of a provider ERCP report card.

Methods: At two referral centers, endoscopy documentation software was modified to generate provider alerts prior to finalizing the note. The alerts reminded the provider to document the following components in a standardized manner: indication, altered anatomy, prior interventions, and QIs deemed high priority by society consensus, study authors, or both. Adherence rates for each QI were calculated in aggregate and by provider via data extraction directly from the procedure documentation software. Medical records were reviewed manually to measure the accuracy of automated data extraction. Accuracy of automated measurement for each QI was calculated against results derived by manual review.

Results: During the 9-month study period, 1,376 ERCP procedures were completed by 8 providers. Manual medical record review confirmed high (98-100%) accuracy of automatic extraction of ERCP QIs from the endoscopy report, including cannulation rate of the native papilla and complete extraction of common bile duct stones. An ERCP report card was generated, allowing for individual comparison of adherence to ERCP QIs with colleagues at their institution and others.

Conclusion: In this pilot study, use of mandatory, structured data fields within clinical ERCP reports permit the accurate measurement of high priority ERCP QIs and the subsequent generation of interval report cards.
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http://dx.doi.org/10.1016/j.tige.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078858PMC
January 2021

The key to reducing residual or recurrent adenoma after duodenal EMR is remembering to spice up the rim.

Gastrointest Endosc 2021 06 23;93(6):1381-1383. Epub 2021 Apr 23.

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.

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http://dx.doi.org/10.1016/j.gie.2021.01.038DOI Listing
June 2021

CRL4 is a master regulator of D-type cyclins.

Nature 2021 Apr 14;592(7856):789-793. Epub 2021 Apr 14.

Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.

D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer, but the mechanisms that regulate their turnover are still being debated. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4 (also known as CRL4) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR-Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.
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http://dx.doi.org/10.1038/s41586-021-03445-yDOI Listing
April 2021

Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors.

Eur J Med Chem 2021 Jul 1;219:113419. Epub 2021 Apr 1.

Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address:

The pathogenesis of Alzheimer's disease (AD) has been associated with dysregulation of histone deacetylases (HDACs). Previously, acridine-based HDAC inhibitors have shown potential in ameliorating HDAC activity and enhancing neurite outgrowth. In this study, the acridine ring was modified using various phenothiazine derivatives. Several resulting compounds exhibited potent enzyme-inhibiting activity towards class II HDACs when compared to the clinically approved HDAC inhibitor SAHA. Compound 4f demonstrated the highest class II HDAC inhibition (IC = 4.6-600 nM), as well as promotion of neurite outgrowth. Importantly, compound 4f displayed no cytotoxicity against neuron cells. Compound 4f was further evaluated for cellular effects. Altogether, these findings show a potential strategy in HDAC inhibition for treatment of the neurological disease.
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http://dx.doi.org/10.1016/j.ejmech.2021.113419DOI Listing
July 2021

A Unique Carboxylic-Acid Hydrogen-Bond Network (CAHBN) Confers Glutaminyl Cyclase Activity on M28 Family Enzymes.

J Mol Biol 2021 Jun 25;433(13):166960. Epub 2021 Mar 25.

Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan. Electronic address:

Proteins with sequence or structure similar to those of di-Zn exopeptidases are usually classified as the M28-family enzymes, including the mammalian-type glutaminyl cyclases (QCs). QC catalyzes protein N-terminal pyroglutamate formation, a posttranslational modification important under many physiological and pathological conditions, and is a drug target for treating neurodegenerative diseases, cancers and inflammatory disorders. Without functional characterization, mammalian QCs and their orthologs remain indistinguishable at the sequence and structure levels from other M28-family proteins, leading to few reported QCs. Here, we show that a low-barrier carboxylic-acid hydrogen-bond network (CAHBN) is required for QC activity and discriminates QCs from M28-family peptidases. We demonstrate that the CAHBN-containing M28 peptidases deposited in the PDB are indeed QCs. Our analyses identify several thousands of QCs from the three domains of life, and we enzymatically and structurally characterize several. For the first time, the interplay between a CAHBN and the binuclear metal-binding center of mammalian QCs is made clear. We found that the presence or absence of CAHBN is a key discriminator for the formation of either the mono-Zn QCs or the di-Zn exopeptidases. Our study helps explain the possible roles of QCs in life.
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http://dx.doi.org/10.1016/j.jmb.2021.166960DOI Listing
June 2021

γδ T cells regulate the intestinal response to nutrient sensing.

Science 2021 03;371(6535)

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.
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http://dx.doi.org/10.1126/science.aba8310DOI Listing
March 2021

Automatic deep learning-based pleural effusion classification in lung ultrasound images for respiratory pathology diagnosis.

Phys Med 2021 Mar 8;83:38-45. Epub 2021 Mar 8.

School of Clinical Sciences, Queensland University of Technology, Gardens Point Campus, 2 George St, Brisbane 4000, QLD, Australia; Centre for Biomedical Technologies (CBT), Queensland University of Technology, Brisbane, Queensland, Australia. Electronic address:

Lung ultrasound (LUS) imaging as a point-of-care diagnostic tool for lung pathologies has been proven superior to X-ray and comparable to CT, enabling earlier and more accurate diagnosis in real-time at the patient's bedside. The main limitation to widespread use is its dependence on the operator training and experience. COVID-19 lung ultrasound findings predominantly reflect a pneumonitis pattern, with pleural effusion being infrequent. However, pleural effusion is easy to detect and to quantify, therefore it was selected as the subject of this study, which aims to develop an automated system for the interpretation of LUS of pleural effusion. A LUS dataset was collected at the Royal Melbourne Hospital which consisted of 623 videos containing 99,209 2D ultrasound images of 70 patients using a phased array transducer. A standardized protocol was followed that involved scanning six anatomical regions providing complete coverage of the lungs for diagnosis of respiratory pathology. This protocol combined with a deep learning algorithm using a Spatial Transformer Network provides a basis for automatic pathology classification on an image-based level. In this work, the deep learning model was trained using supervised and weakly supervised approaches which used frame- and video-based ground truth labels respectively. The reference was expert clinician image interpretation. Both approaches show comparable accuracy scores on the test set of 92.4% and 91.1%, respectively, not statistically significantly different. However, the video-based labelling approach requires significantly less effort from clinical experts for ground truth labelling.
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http://dx.doi.org/10.1016/j.ejmp.2021.02.023DOI Listing
March 2021

Selection of patients for large mailed fecal immunochemical test colorectal cancer screening outreach programs: A systematic review.

J Med Screen 2021 Mar 8:969141321997482. Epub 2021 Mar 8.

Division of Gastroenterology, University of California, San Francisco, CA, USA.

Objective: Digital health care offers an opportunity to scale and personalize cancer screening programs, such as mailed outreach for colorectal cancer (CRC) screening. However, studies that describe the patient selection strategy and process for CRC screening are limited. Our objective was to evaluate implementation strategies for selecting patients for CRC screening programs in large health care systems.

Methods: We conducted a systematic review of 30 studies along with key informant surveys and interviews to describe programmatic implementation strategies for selecting patients for CRC screening. PubMed and Embase were searched since inception through December 2018, and hand searches were performed of the retrieved reference lists but none were incorporated ( = 0). No language exclusions were applied.

Results: Common criteria for outreach exclusion included: being up-to-date with routine CRC screening ( = 22), comorbidities ( = 20), and personal history ( = 22) or family history of cancer ( = 9). Key informant surveys and interviews were performed ( = 28) to understand data sources and practices for patient outreach selection, and found that 13 studies leveraged electronic medical care records, 10 studies leveraged a population registry (national, municipal, community, health), 4 studies required patient opt-in, and 1 study required primary care provider referral. Broad ranges in fecal immunochemical test completion were observed in community clinic ( = 8, 31.0-59.6%), integrated health system ( = 5, 21.2-82.7%), and national regional CRC screening programs ( = 17, 23.0-64.7%). Six studies used technical codes, and four studies required patient self-reporting from a questionnaire to participate.

Conclusion: This systematic review provides health systems with the diverse outreach practices and technical tools to support efforts to automate patient selection for CRC screening outreach.
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http://dx.doi.org/10.1177/0969141321997482DOI Listing
March 2021

DMTMM-Mediated Intramolecular Cyclization of Acidic Residues in Peptides/Proteins.

ACS Omega 2021 Feb 5;6(7):4708-4718. Epub 2021 Feb 5.

Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.

The formation of succinimide in proteins has attracted considerable attention in protein aging and biopharmaceutical research. The succinimide formation occurs spontaneously in proteins and is prone to hydrolysis to yield aspartate and isoaspartate, resulting in altered protein functions. Herein, we demonstrated that the coupling reagent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) can mediate intramolecular cyclization of aspartic acid to form succinimide efficiently in the LL37-derived short antimicrobial peptide KR12. The formation of succinimide in KR12 was confirmed by liquid chromatography tandem mass spectrometry and nuclear magnetic resonance. Moreover, the succinimide-containing KR12 displayed decreased antimicrobial activity, helicity, and serum stability in comparison with unmodified KR12. The succinimide formation usually changes the protein structure and function, and only in rare cases, it can help to maintain the protein stability. In addition to succinimide, DMTMM can also mediate intraresidue cyclization of N-terminal glutamate to form pyroglutamate. Our work thus provides a convenient and efficient method for preparation of succinimide/pyroglutamate-containing peptides, which can be used for studying their impact on peptide/protein function.
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http://dx.doi.org/10.1021/acsomega.0c05503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905807PMC
February 2021

COVID-19 vaccines for patients with cancer: benefits likely outweigh risks.

J Hematol Oncol 2021 02 27;14(1):38. Epub 2021 Feb 27.

Pelotonia Institute for Immuno-Oncology, The OH State University Comprehensive Cancer Center - James, Columbus, OH, USA.

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.
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http://dx.doi.org/10.1186/s13045-021-01046-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910769PMC
February 2021

Determining the feasibility of an index of the social determinants of health using data from public sources.

Inform Health Soc Care 2021 Jun 25;46(2):205-217. Epub 2021 Feb 25.

Institute for Public Health and Medicine, Center for Health Services and Outcomes Research, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Examining the feasibility of developing an index measure for the social determinants of health using public data is needed. We examined these characteristics at the ZIP code in California and New York using public data extracted from the US Census, American Community Survey, the USDA Food Research Access Atlas, and the Dartmouth Atlas. We conducted a retrospective study from 2000 to 2017. The main outcome was a novel index measure representing six domains (economic stability, neighborhood and physical environment, education, community and social context, food access, and health care) and encompassing 13 items. The index measure at the ZIP code was created using principal component analysis, normalized to "0" worse and "1" better in California (ZIP codes n = 1,447 to 1,515) and New York (ZIP codes n = 1,211 to 1,298). We assessed the reliability and conducted a nonparametric comparison to the Robert Wood Johnson Foundation County Health Rankings, Area Deprivation Index, Social Deprivation Index, and GINI Index. These measures shared similarities and differences with the novel measure. Mapping of this novel measure showed regional variation. As a result, developing a universal social determinants of health measure is feasible and more research is needed to link it to health outcomes.
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http://dx.doi.org/10.1080/17538157.2021.1880413DOI Listing
June 2021

Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

Ageing Res Rev 2021 05 18;67:101301. Epub 2021 Feb 18.

Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.
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http://dx.doi.org/10.1016/j.arr.2021.101301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043243PMC
May 2021

Endoscopic Submucosal Dissection in North America: A Large Prospective Multicenter Study.

Gastroenterology 2021 Jun 19;160(7):2317-2327.e2. Epub 2021 Feb 19.

Division of Gastroenterology and Hepatology, University of Florida, Gainesville, Florida.

Background And Aims: Endoscopic submucosal dissection (ESD) in Asia has been shown to be superior to endoscopic mucosal resection (EMR) and surgery for the management of selected early gastrointestinal cancers. We aimed to evaluate technical outcomes of ESD in North America.

Methods: We conducted a multicenter prospective study on ESD across 10 centers in the United States and Canada between April 2016 and April 2020. End points included rates of en bloc resection, R0 resection, curative resection, adverse events, factors associated with failed resection, and recurrence post-R0 resection.

Results: Six hundred and ninety-two patients (median age, 66 years; 57.8% were men) underwent ESD (median lesion size, 40 mm; interquartile range, 25-52 mm) for lesions in the esophagus (n = 181), stomach (n = 101), duodenum (n = 11), colon (n = 211) and rectum (n = 188). En bloc, R0, and curative resection rates were 91.5%, 84.2%, and 78.3%, respectively. Bleeding and perforation were reported in 2.3% and 2.9% of the cases, respectively. Only 1 patient (0.14%) required surgery for adverse events. On multivariable analysis, severe submucosal fibrosis was associated with failed en bloc, R0, and curative resection and higher risk for adverse events. Overall recurrence was 5.8% (31 of 532) at a mean follow-up of 13.3 months (range, 1-60 months).

Conclusions: In this large multicenter prospective North American experience, we demonstrate that ESD can be performed safely, effectively, and is associated with a low recurrence rate. The technical resection outcomes achieved in this study are in line with the current established consensus quality parameters and further support the implementation of ESD for the treatment of select gastrointestinal neoplasms; ClinicalTrials.gov, Number: NCT02989818.
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http://dx.doi.org/10.1053/j.gastro.2021.02.036DOI Listing
June 2021

Through-the-Scope Clips Are Indispensable in Treating Deep Mural Injury From Colorectal EMR.

Authors:
Andrew Y Wang

Clin Gastroenterol Hepatol 2021 Feb 17. Epub 2021 Feb 17.

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia.

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http://dx.doi.org/10.1016/j.cgh.2021.02.023DOI Listing
February 2021
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