Publications by authors named "Peter Lin"

441 Publications

Small Cell Size Circulating Aneuploid Cells as a Biomarker of Prognosis in Resectable Non-Small Cell Lung Cancer.

Front Oncol 2021 3;11:590952. Epub 2021 Mar 3.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Objective: The size distribution of circulating aneuploid cells (CACs) and its clinical significance were investigated in resectable non-small cell lung cancer (NSCLC).

Patients And Methods: A total of 50 patients with resectable NSCLC were enrolled in this study. Blood samples (50 pre-surgery and 35 post-surgery) were collected and used for the detection of CAC chromosome 8 heteroploidy through the subtraction enrichment and immunostaining fluorescence hybridization (SE-iFISH) method.

Results: Less than 20% small cell size and more than 80% large cell size CACs were detected. Karyotypes, including triploid, tetraploid, and multiploid, had varying distributions. The triploid subtype accounted for the majority of small cell size CACs, whereas the multiploid subtype accounted for the majority of large cell size CACs. We found that total small cell size and triploid small cell size CACs, but not large cell size CACs, derived from pre-surgery samples, were associated with shorter disease-free survival. Moreover, total small cell size and triploid small cell size CACs were associated with higher TNM stage and recurrence. Nevertheless, the variation between pre- and post-surgery CACs was not related to survival among patients with resectable NSCLC.

Conclusions: Pre-surgery small cell size CACs, especially the triploid subtype, could be regarded as a potential prognostic biomarker for patients with resectable NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.590952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968455PMC
March 2021

INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia.

Neurobiol Dis 2021 Jun 22;153:105303. Epub 2021 Feb 22.

Department of Radiology & Imaging Sciences, IUSM, Indianapolis, IN, USA. Electronic address:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. We performed differential gene expression analysis to investigate INPP5D expression in AD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.
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http://dx.doi.org/10.1016/j.nbd.2021.105303DOI Listing
June 2021

[Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

Lancet 2021 Feb 11;397(10276):797-804. Epub 2021 Feb 11.

Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Eastern Health, Melbourne, VIC, Australia.

Background: Lutetium-177 [Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.

Methods: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [Ga]Ga-PSMA-11 and 2-flourine-18[F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.

Findings: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [Lu]Lu-PSMA-617.

Interpretation: [Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.

Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
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http://dx.doi.org/10.1016/S0140-6736(21)00237-3DOI Listing
February 2021

Smartwatch inertial sensors continuously monitor real-world motor fluctuations in Parkinson's disease.

Sci Transl Med 2021 Feb;13(579)

Apple Inc., Cupertino, CA 95014, USA.

Longitudinal, remote monitoring of motor symptoms in Parkinson's disease (PD) could enable more precise treatment decisions. We developed the Motor fluctuations Monitor for Parkinson's Disease (MM4PD), an ambulatory monitoring system that used smartwatch inertial sensors to continuously track fluctuations in resting tremor and dyskinesia. We designed and validated MM4PD in 343 participants with PD, including a longitudinal study of up to 6 months in a 225-subject cohort. MM4PD measurements correlated to clinical evaluations of tremor severity (ρ = 0.80) and mapped to expert ratings of dyskinesia presence ( < 0.001) during in-clinic tasks. MM4PD captured symptom changes in response to treatment that matched the clinician's expectations in 94% of evaluated subjects. In the remaining 6% of cases, symptom data from MM4PD identified opportunities to make improvements in pharmacologic strategy. These results demonstrate the promise of MM4PD as a tool to support patient-clinician communication, medication titration, and clinical trial design.
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http://dx.doi.org/10.1126/scitranslmed.abd7865DOI Listing
February 2021

Non-vitamin K antagonist oral anticoagulant (NOAC) use and dosing in Canadian practice: Insights from the optimising pharmacotherapy in the management approach to lowering risk in atrial fibrillation (OPTIMAL AF) Programme.

Int J Clin Pract 2020 Dec 27;74(12):e13625. Epub 2020 Aug 27.

University of Toronto, Toronto, ON, Canada.

Aims: To estimate the rate of non-vitamin K oral anticoagulant (NOAC) dosing that is lower- and higher-than-recommended and to describe the reasons for NOAC dose discordance with Health Canada prescribing information.

Methods: The OPTIMAL AF Programme was an observational cohort quality assessment initiative in which primary and specialty care physicians in eight provinces provided a snapshot of their anticoagulated non-valvular atrial fibrillation (NVAF) patients through either an electronic medical record (EMR) system or standardised, paper-based data collection methods.

Results: Data on 1681 NVAF patients receiving oral anticoagulation (OAC) for stroke prevention was provided by 102 physicians. A NOAC was prescribed in 1379 patients (8%). The standard recommended dose was prescribed in 849 (76%) and reduced dose in 264 (24%). Concordance of the reduced dose with Health Canada prescribing information occurred in 154 patients (58%). The standard dose was concordant in 805 (95%). The main reasons for the use of discordant reduced doses were age of 80 years or more, elevated creatinine, prior bleeding or dose recommended by specialist.

Discussion And Conclusion: The vast majority of Canadian patients meeting the Canadian Cardiovascular Society (CCS) guideline recommendations for OAC to decrease AF-related stroke risk were receiving product monograph-concordant NOAC dosing (85%). Nonetheless, this highlights the fact that an important proportion of patients were prescribed doses that are discordant and opportunities remain to improve NOAC dosing to optimise stroke prevention.
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http://dx.doi.org/10.1111/ijcp.13625DOI Listing
December 2020

Global survey investigating causes of treatment inertia in type 2 diabetes cardiorenal risk management.

J Diabetes Complications 2021 Mar 26;35(3):107813. Epub 2020 Nov 26.

Hausärztliche Gemeinschaftspraxis, Köln, Germany.

Aim: To explore reasons behind treatment inertia in current approaches to early cardiorenal risk management in type 2 diabetes (T2D).

Methods: A global, web-based, quantitative panel survey of primary care physicians (PCPs) and primary care diabetes specialists treating people living with T2D. The questions covered current management of T2D, particularly the use of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors as second-/third-line therapies.

Results: Of 1677 respondents from 18 countries who completed the survey, 73.4% were responsible for second-/third-line therapy initiation. Two thirds had modified treatment decisions based on recent cardiovascular outcomes trials (CVOTs). Respondents cited restricted access to therapies and limits on regular appointments as the greatest barriers to second-/third-line therapy prescription. Although 81.6% agreed that early intensification to second-/third-line therapies is associated with clinical benefits, 46.1% of respondents still reserve these for later lines of therapy, and 23.8% would not consider changing therapeutic approach in patients with well-controlled T2D but increasing cardiovascular risk.

Conclusions: Substantial barriers still prevent optimization of primary setting T2D patient care. Education programs which enable PCPs to translate CVOT evidence into clinical benefits for patients with T2D could address many of the remaining knowledge gaps identified.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107813DOI Listing
March 2021

Does management of lipid lowering differ between specialists and primary care: Insights from GOAL Canada.

Int J Clin Pract 2021 Apr 14;75(4):e13861. Epub 2020 Dec 14.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Background: We studied whether significant differences in care gaps exist between specialists and primary care physicians (PCPs).

Methods: GOAL Canada enrolled patients with CVD or familial hypercholesterolemia (FH) and LDL-C > 2.0 mmol/L despite maximally tolerated statin therapy. During follow-up, physicians received online reminders of treatment recommendations based on Canadian Guidelines.

Results: A total of 177 physicians (58% PCPs) enrolled 2009 patients; approximately half of the patients were enrolled by each physician group. Patients enrolled by specialists were slightly older (mean age 63 years vs 62), female (45% vs 40%), Caucasian (77% vs 65%), and had a slightly higher systolic pressure and lower heart rate. Patients enrolled by specialists had less frequent history of FH, diabetes, hypertension, chronic kidney disease and liver disease but more frequent history of coronary artery disease, atrial fibrillation and premature family history of CVD. There was no significant baseline difference in LDL-C, HDL-C or non-HDL-C, although total cholesterol and triglycerides were slightly higher in patients managed by PCPs. At baseline, PCPs were more likely to use statins (80% vs 73%, P = .0002) and other therapies such as niacin or fibrate (10% vs 6%, P = .0006) but similar use of ezetimibe (24% vs 27%, P = .15). At the end of follow-up, specialists used less statins (70% vs 77%, P = .0005) and other therapies (6% vs 10%, P = .007) but more ezetimibe (45% vs 38%, P = .01) and the same frequency of PCSK9i (28% vs 27%, P = .65). The proportion of patients achieving the recommended LDL-C level of 2.0 mmol/L or below (primary endpoint) was similar at last available visit between specialists and PCPs (44% vs 42%, P = .32).

Conclusion: Despite minor differences in the clinical profile of their patients, both PCPs and specialists actively participate in the management of lipid-lowering therapy in high-risk CVD patients and experience similar challenges and care gaps.
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http://dx.doi.org/10.1111/ijcp.13861DOI Listing
April 2021

COVID-19-Associated Nonocclusive Fibrin Microthrombi in the Heart.

Circulation 2021 01 16;143(3):230-243. Epub 2020 Nov 16.

Department of Laboratory Medicine and Pathology (M.C.B., N.A.B., A.J.L., M.-C.A., M.P.A., A.C.R., C.E.H., R.A.Q., R.M., B.R.K., P.T.L., J.J.M.), Mayo Clinic, Rochester, MN.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection.

Methods: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction.

Results: Male sex was more common in the COVID-19 group (=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (=0.69, =1.00, =0.46, =0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations.

Conclusions: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805556PMC
January 2021

Evaluation of Concordance Between Original Death Certifications and an Expert Panel Process in the Determination of Sudden Unexplained Death in Childhood.

JAMA Netw Open 2020 10 1;3(10):e2023262. Epub 2020 Oct 1.

NYU Grossman School of Medicine, New York, New York.

Importance: The true incidence of sudden unexplained death in childhood (SUDC), already the fifth leading category of death among toddlers by current US Centers for Disease Control and Prevention estimates, is potentially veiled by the varied certification processes by medicolegal investigative offices across the United States.

Objective: To evaluate the frequency of SUDC incidence, understand its epidemiology, and assess the consistency of death certification among medical examiner and coroner offices in the US death investigation system.

Design, Setting, And Participants: In this case series, 2 of 13 forensic pathologists (FPs) conducted masked reviews of 100 cases enrolled in the SUDC Registry and Research Collaborative (SUDCRRC). Children who died aged 11 months to 18 years from 36 US states, Canada, and the United Kingdom had been posthumously enrolled in the SUDCRRC by family members from 2014 to 2017. Comprehensive data from medicolegal investigative offices, clinical offices, and family members were reviewed. Data analysis was conducted from December 2014 to June 2020.

Main Outcomes And Measures: Certified cause of death (COD) characterized as explained (accidental or natural) or unexplained, as determined by SUDCRRC masked review process.

Results: In this study of 100 cases of SUDC (mean [SD] age, 32.1 [31.8] months; 58 [58.0%] boys; 82 [82.0%] White children; 92 [92.0%] from the United States), the original pathologist certified 43 cases (43.0%) as explained COD and 57 (57.0%) as unexplained COD. The SUDCRRC review process led to the following certifications: 16 (16.0%) were explained, 7 (7.0%) were undetermined because of insufficient data, and 77 (77.0%) were unexplained. Experts disagreed with the original COD in 40 cases (40.0%). These data suggest that SUDC incidence is higher than the current Centers for Disease Control and Prevention estimate (ie, 392 deaths in 2018).

Conclusions And Relevance: To our knowledge, this is the first comprehensive masked forensic pathology review process of sudden unexpected pediatric deaths, and it suggests that SUDC may often go unrecognized in US death investigations. Some unexpected pediatric deaths may be erroneously attributed to a natural or accidental COD, negatively affecting surveillance, research, public health funding, and medical care of surviving family members. To further address the challenges of accurate and consistent death certification in SUDC, future studies are warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.23262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599447PMC
October 2020

Multiparametric laryngeal assessment of the effect of thalamic deep brain stimulation on essential vocal tremor.

Parkinsonism Relat Disord 2020 12 13;81:106-112. Epub 2020 Oct 13.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Objective: EVT is a refractory voice disorder that significantly affects quality of life. This work aims to conduct a multiparametric assessment of the effect of deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) on essential vocal tremor (EVT) and investigate the relation between DBS lead location and EVT outcomes.

Methods: Nine participants underwent DBS for essential tremor and were diagnosed with co-occurring EVT in this prospective cohort study. Objective measurements including acoustic evaluation of vocal fundamental frequency (F0) and intensity modulation and subjective measurements including physiologic evaluation of the oscillatory movement of the laryngeal muscles and vocal tract and perceptual ratings of tremor severity were collected PRE and POST DBS. Finally, we investigated the relation between DBS lead location and EVT outcomes.

Results: Acoustic modulations of F0 and intensity were significantly improved POST DBS. Physiologic assessment showed a POST DBS reduction of oscillatory movement in the laryngeal muscles and vocal tract, but not significantly. Listener and participant perception, of EVT severity was also significantly reduced. Finally, our results indicate better EVT control with increased distance to midline of left VIM thalamic stimulation.

Conclusions: By employing a battery of objective and subjective measures, our study supports the benefit of DBS for the treatment of EVT and specifies the acoustic and physiologic mechanisms that mediate its positive effect. We further provide preliminary results on the relation between lead location and EVT outcomes, laying the foundation for future studies to clarify the optimal DBS target for the treatment of EVT.
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http://dx.doi.org/10.1016/j.parkreldis.2020.10.026DOI Listing
December 2020

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice.

Mol Neurodegener 2020 10 28;15(1):62. Epub 2020 Oct 28.

Paul and Carole Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN, 46202, USA.

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer's disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia.

Methods: To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2 and Trem2 mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.

Results: While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2 mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity.

Conclusion: Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2 and Trem2 mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.
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http://dx.doi.org/10.1186/s13024-020-00409-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594478PMC
October 2020

Novel 5-point 18-FDG-PET/CT visual scoring system for assessing treatment response in patients with oesophageal or gastro-oesophageal junction carcinoma.

J Med Imaging Radiat Oncol 2021 Feb 15;65(1):23-37. Epub 2020 Oct 15.

University of New South Wales, Sydney, New South Wales, Australia.

Introduction: The purpose of this study was to investigate the prognostic utility and reproducibility of a qualitative 5-point 18-fluorodeoxyglucose (FDG)-PET primary visual score (PVS) in patients with oesophageal and gastro-oesophageal junction (GOJ) cancer.

Methods: This was a retrospective review of patients with histologically proven oesophageal or GOJ cancer who received curative intent therapy. Clinical, pathological and imaging data were extracted from electronic medical records. Patients were required to have pre-treatment and post-treatment FDG-PET scans, that were evaluated with a 5-point primary visual score (prePVS, postPVS). The changes in PVS (ΔPVS) were correlated with progression-free survival and overall survival. Interobserver variability was assessed using Cohen's Kappa intraclass correlation and agreement.

Results: Sixty-seven patients were retrospectively identified. Two (3%), 36 (54%) and 29 (43%) of the patients had stage I, II and III disease respectively. Twenty-five (37%) patients had squamous cell carcinoma. Thirty-seven (55%) patients proceeded onto surgical resection. postPVS was associated with both PFS (P = 0.013) and OS (P = 0.0002). ΔPVS predicted for PFS (P = 0.002) and OS (P = 0.0003). When thresholds of response were considered, agreement was 80.6% (K = 0.78) and 74.6% (K = 0.69) for postPVS and ΔPVS respectively.

Conclusion: Qualitative assessment of oesophageal and GOJ cancers utilising FDG-PET is reproducible and may be able to prognosticate outcomes in patients undergoing treatment. Prospective validation is required.
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http://dx.doi.org/10.1111/1754-9485.13110DOI Listing
February 2021

Metabolic Defects Caused by High-Fat Diet Modify Disease Risk through Inflammatory and Amyloidogenic Pathways in a Mouse Model of Alzheimer's Disease.

Nutrients 2020 Sep 29;12(10). Epub 2020 Sep 29.

Stark Neurosciences Research Institute, Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

High-fat diet (HFD) has been shown to accelerate Alzheimer's disease (AD) pathology, but the exact molecular and cellular mechanisms remain incompletely understood. Moreover, it is unknown whether AD mice are more susceptible to HFD-induced metabolic dysfunctions. To address these questions, we used 5xFAD mice as an Alzheimer's disease model to study the physiological and molecular underpinning between HFD-induced metabolic defects and AD pathology. We systematically profiled the metabolic parameters, the gut microbiome composition, and hippocampal gene expression in 5xFAD and wild type (WT) mice fed normal chow diet and HFD. HFD feeding impaired energy metabolism in male 5xFAD mice, leading to increased locomotor activity, energy expenditure, and food intake. 5xFAD mice on HFD had elevated circulating lipids and worsened glucose intolerance. HFD caused profound changes in gut microbiome compositions, though no difference between genotype was detected. We measured hippocampal mRNAs related to AD neuropathology and neuroinflammation and showed that HFD elevated the expression of apoptotic, microglial, and amyloidogenic genes in 5xFAD mice. Pathway analysis revealed that differentially regulated genes were involved in insulin signaling, cytokine signaling, cellular stress, and neurotransmission. Collectively, our results showed that 5xFAD mice were more susceptible to HFD-induced metabolic dysregulation and suggest that targeting metabolic dysfunctions can ameliorate AD symptoms via effects on insulin signaling and neuroinflammation in the hippocampus.
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http://dx.doi.org/10.3390/nu12102977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600118PMC
September 2020

Update to Evidence-Based Secondary Prevention Strategies After Acute Coronary Syndrome.

CJC Open 2020 Sep 10;2(5):402-415. Epub 2020 Apr 10.

St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

A recent acute coronary syndrome provides an opportunity to optimise secondary prevention strategies to reduce the risk of future cardiovascular events. This review provides an updated synopsis of current evidence-based approaches. New clinical trial data on the use of antiplatelet and anticoagulants allow choices of the selection and duration of treatment. Lipid lowering after an acute coronary syndrome is now enhanced, with proprotein convertase subtilisin-kexin type 9 inhibitors providing added benefit on top of statin and ezetimibe treatment in high-risk patients. In addition, a recent trial of icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, addresses residual risk in patients with elevated triglycerides already treated with statins. The use of both sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes reduces cardiovascular events independently of glucose lowering.
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http://dx.doi.org/10.1016/j.cjco.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499366PMC
September 2020

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.

Eur Heart J 2020 Oct;41(39):3827-3835

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Aims: Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described.

Methods And Results: In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.

Conclusions: In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.
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http://dx.doi.org/10.1093/eurheartj/ehaa664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543528PMC
October 2020

The Spectrum of Histopathologic Findings in Lungs of Patients With Fatal Coronavirus Disease 2019 (COVID-19) Infection.

Arch Pathol Lab Med 2021 01;145(1):11-21

Department of Laboratory Medicine and Pathology (Roden, Bois, Aubry, Alexander, Hagen, Lin, Quinton, Maleszewski, Boland), Mayo Clinic, Rochester, Minnesota.

Context.—: Respiratory failure appears to be the ultimate mechanism of death in most patients with severe coronavirus disease 2019 (COVID-19) infection. Studies of postmortem COVID-19 lungs largely report diffuse alveolar damage and capillary fibrin thrombi, but we have also observed other patterns.

Objective.—: To report demographic and radiographic features along with macroscopic, microscopic, and microbiologic postmortem lung findings in patients with COVID-19 infections.

Design.—: Patients with confirmed COVID-19 infection and postmortem examination (March 2020-May 2020) were included. Clinical findings were abstracted from medical records. Lungs were microscopically reviewed independently by 4 thoracic pathologists. Imaging studies were reviewed by a thoracic radiologist.

Results.—: Eight patients (7 men, 87.5%; median age, 79 years; range, 69-96 years) died within a median of 17 days (range, 6-100 days) from onset of symptoms. The median lung weight was 1220 g (range, 960-1760 g); consolidations were found in 5 patients (62.5%) and gross thromboemboli were noted in 1 patient (12.5%). Histologically, all patients had acute bronchopneumonia; 6 patients (75%) also had diffuse alveolar damage. Two patients (25%) had aspiration pneumonia in addition. Thromboemboli, usually scattered and rare, were identified in 5 patients (62.5%) in small vessels and in 2 of these patients also in pulmonary arteries. Four patients (50%) had perivascular chronic inflammation. Postmortem bacterial lung cultures were positive in 4 patients (50%). Imaging studies (available in 4 patients) were typical (n = 2, 50%), indeterminate (n = 1, 25%), or negative (n = 1, 25%) for COVID-19 infection.

Conclusions.—: Our study shows that patients infected with COVID-19 not only have diffuse alveolar damage but also commonly have acute bronchopneumonia and aspiration pneumonia. These findings are important for management of these patients.
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http://dx.doi.org/10.5858/arpa.2020-0491-SADOI Listing
January 2021

Melody Valve Endocarditis Due to Rothia dentocariosa: A Diagnostic Challenge.

Cureus 2020 Jun 26;12(6):e8840. Epub 2020 Jun 26.

Cardiology, Saint Luke's Mid-America Heart Institute, Kansas City, USA.

Recently, there have been several advances in the field of adult congenital heart disease, such as the percutaneous pulmonic valve implantation (PPVI) to treat right ventricular outflow obstruction. Complications from this technique are seldom but essential to understand. We present a case of a 37-year-old Caucasian male with complicated congenital heart disease, including prior Melody valve implantation, who presented to our hospital with recurrent episodes of pneumonia of two months duration. He was diagnosed with prosthetic valve endocarditis (PVE) from an unusual organism, . He eventually underwent surgical replacement of the infected valve. Our report is the first case of Melody valve endocarditis due to reported from the United States.
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http://dx.doi.org/10.7759/cureus.8840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386052PMC
June 2020

Sudden Unexpected Death in MELAS Syndrome Due to Diabetic Ketoacidosis.

Am J Forensic Med Pathol 2020 Dec;41(4):331-332

From the Department of Laboratory Medicine and Pathology, Mayo Clinic.

We present a case report of a 25 year-old man with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome, who died suddenly and unexpectedly from diabetic ketoacidosis. This case report illustrates why it is important for medical examiners to be familiar with the clinical and autopsy features of MELAS syndrome and to be aware of the common complications, which may lead to sudden unexpected death.
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http://dx.doi.org/10.1097/PAF.0000000000000563DOI Listing
December 2020

Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis.

Authors:
Peter Ping Lin

Cells 2020 06 24;9(6). Epub 2020 Jun 24.

Cytelligen, San Diego, CA 92121, USA.

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from "cancerization of stromal endothelial cells" and "endothelialization of carcinoma cells" in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31 CTECs, together with their counterpart CD31 circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.
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http://dx.doi.org/10.3390/cells9061539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349247PMC
June 2020

Formalin pigment artifact deposition in autopsy tissue: predisposing factors, patterns of distribution and methods for removal.

Forensic Sci Med Pathol 2020 09 23;16(3):435-441. Epub 2020 Mar 23.

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.

Formalin pigment deposition is a known artifact of autopsy histology, often anecdotally associated with decomposition of bodies. However, there is minimal data within the forensic literature demonstrating an association between formalin pigment deposition and length of postmortem interval. Furthermore, there is minimal data concerning other predisposing factors and patterns of distribution of formalin pigment deposition. In this study, we compare the amount and patterns of formalin deposition on histology slides from three categories of death: 1) decomposed bodies, 2) critically ill at time of death, and 3) sudden cardiac death. We also compare the effectiveness of two relatively simple histology laboratory methods to remove formalin pigment deposition from histology slides. Amongst the three categories of death, formalin deposition was highest in the decomposed category, second highest in the critically ill category, and lowest in the sudden cardiac death category. The organs most severely affected by formalin deposition were liver/spleen/pancreas and kidneys, and the organs least affected were brain and lung. Formalin pigment deposition correlated with length of postmortem interval. Histologic patterns of formalin deposition included the endothelial lining of vessels, perinuclear compartment of neurons and myocytes, and the basal epithelial compartment of renal tubular epithelial cells. The alcoholic ammonium hydroxide method (AAH) was slightly more effective than the alkylphenol ethoxylate (APE) method for removing formalin pigment, though both methods were effective. Because formalin pigment is strongly refractile under polarized light, a polarization filter can also be useful for distinguishing formalin pigment from other pigments.
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http://dx.doi.org/10.1007/s12024-020-00240-5DOI Listing
September 2020

GOAL Canada: Physician Education and Support Can Improve Patient Management.

CJC Open 2020 Mar 28;2(2):49-54. Epub 2019 Dec 28.

Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Despite the widespread use of statins, approximately 40% to 50% of Canadian patients with known cardiovascular disease do not achieve the low-density lipoprotein cholesterol (LDL-C) goal. uidelines riented pproach to ipid lowering (GOAL) is an investigator-initiated study aiming to ascertain the use of second- and third-line therapy and its impact on LDL-C goal achievement in a real-world setting.

Methods: GOAL enrolled patients with clinical vascular disease or familial hypercholesterolemia and LDL-C > 2.0 mmol/L despite maximally tolerated statin therapy. During follow-up, physicians managed patients as clinically indicated but with online reminders of guideline recommendations.

Results: Of 2009 patients enrolled (median age 63 years, 42% were female), baseline total cholesterol was 5.5 ± 1.4 mmol/L, LDL-C was 3.3 ± 1.3 mmol/L, non-high-density lipoprotein cholesterol was 4.1 ± 1.4 mmol/L, high-density lipoprotein cholesterol was 1.3 ± 0.4 mmol/L, and triglycerides were 2.0 ± 1.5 mmol/L. Lipid-lowering therapy used at baseline was statin therapy in 76% (with 24% statin intolerant) and ezetimibe in 25%. During follow-up, the proportion of patients achieving an LDL-C level of < 2.0 mmol/L increased significantly to 50.8% as a result of additional lipid-lowering therapy. Patients achieving the recommended LDL-C level were more likely to not be statin intolerant (83.8% vs 70.7%,  0.0001) and to be taking a high-efficacy type and dose of statin (52.4% vs 35.9%, 0.0001). The 3 top reasons for not using the recommended therapy with ezetimibe were patient refusal in 33%, not needed in 22%, and intolerance in 20%, whereas for PCSK9i the reasons were cost in 26%, not needed in 27%, or patient refusal in 25%.

Conclusion: The results indicate the feasibility of optimizing management, resulting in achievement of the guideline-recommended LDL-C level. This has the potential to translate into reductions in cardiovascular morbidity and mortality of Canadian patients.
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http://dx.doi.org/10.1016/j.cjco.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067689PMC
March 2020

Forensic Considerations in a Series of 14 Deaths of Patients with a Left Ventricular Assist Device.

Acad Forensic Pathol 2019 Sep 31;9(3-4):200-211. Epub 2020 Jan 31.

Introduction: To better understand the forensic implications of death with a left ventricular assist device (LVAD), we reviewed all deaths that were reported to a regional medical examiner jurisdiction involving patients who had an LVAD.

Methods: Medical examiner case files between January 2012 and September 2018 were searched for "LVAD" and "left ventricular assist device" to identify deaths that were reported to the medical examiner involving a decedent who had an LVAD at the time of death.

Results: During the study period, a total of 14 deaths were reported to the regional medical examiner involving decedents who had an implanted LVAD at the time of death. The average age at death was 64 years, with a range from 40 to 81 years. The underlying cardiac disease leading to LVAD implantation was ischemic heart disease (n = 9), nonischemic dilated cardiomyopathy (n = 4), and chemotherapy-related cardiotoxicity (n = 1). Of these 14 deaths, 2 deaths were due to loss of power to the LVAD, 1 death was due to traumatic subdural hemorrhage occurring in the setting of anticoagulation therapy required by LVAD implantation, and 1 death was due to femur fracture following a fall.

Discussion: Medical examiners should be familiar with the potential complications of LVADs, especially those complications that may prompt consideration of non-natural manners of death. Medical examiners should also be aware of the tools and investigative strategies that may assist in the investigation of LVAD-related deaths.
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http://dx.doi.org/10.1177/1925362119893459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997991PMC
September 2019

The Role of Urocortins in Intracerebral Hemorrhage.

Biomolecules 2020 01 7;10(1). Epub 2020 Jan 7.

Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 707, Section 3, Zhong-yang Road, Hualien 970, Taiwan.

Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined.
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http://dx.doi.org/10.3390/biom10010096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022917PMC
January 2020

Non-technical skills curriculum incorporating simulation-based training improves performance in colonoscopy among novice endoscopists: Randomized controlled trial.

Dig Endosc 2020 Sep 18;32(6):940-948. Epub 2020 Feb 18.

Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.

Background And Aims: Non-technical skills (NTS), involving cognitive, social and interpersonal skills that complement technical skills, are important for the completion of safe and efficient procedures. We investigated the impact of a simulation-based curriculum with dedicated NTS training on novice endoscopists' performance of clinical colonoscopies.

Methods: A single-blinded randomized controlled trial was conducted at a single center. Novice endoscopists were randomized to a control curriculum or a NTS curriculum. The control curriculum involved a didactic session, virtual reality (VR) simulator colonoscopy training, and integrated scenario practice using a VR simulator, a standardized patient, and endoscopy nurse. Feedback and training were provided by experienced endoscopists. The NTS curriculum group received similar training that included a small-group session on NTS, feedback targeting NTS, and access to a self-reflective NTS checklist. The primary outcome was performance during two clinical colonoscopies, assessed using the Joint Advisory Group Direct Observation of Procedural Skills (JAG DOPS) tool.

Results: Thirty-nine participants completed the study. The NTS group (n = 21) had superior clinical performance during their first (P < 0.001) and second clinical colonoscopies (P < .0.001), compared to the control group (n = 18). The NTS group performed significantly better on the VR simulator (P < 0.05) and in the integrated scenario (P < 0.05).

Conclusion: Our findings demonstrate that dedicated NTS training led to improved performance of clinical colonoscopies among novices.
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http://dx.doi.org/10.1111/den.13623DOI Listing
September 2020

Thoracic aortic dissection associated with involvement by small lymphocytic lymphoma/chronic lymphocytic leukemia: a possible underappreciated risk factor?

Cardiovasc Pathol 2020 Mar - Apr;45:107179. Epub 2019 Nov 18.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Electronic address:

We report a case of a 77-year-old man with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) thought to be in remission who developed an acute type A thoracic aortic dissection despite no known risk factors for aortic dissection. Surgical pathology evaluation of the aorta specimen removed at surgery showed direct lymphocytic infiltration of the aortic adventitia and media in the region of the aortic dissection. The potential causative role and pathophysiologic mechanisms of SLL/CLL in aortic dissection are discussed.
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http://dx.doi.org/10.1016/j.carpath.2019.107179DOI Listing
June 2020

High negative predictive value of 68Ga PSMA PET-CT for local lymph node metastases in high risk primary prostate cancer with histopathological correlation.

Cancer Imaging 2019 Dec 11;19(1):86. Epub 2019 Dec 11.

Department of Urology, Campbelltown Hospital, Sydney, Australia.

Background: Current guidelines highlight the importance of accurate staging in the management and prognostication of high risk primary prostate cancer. Conventional radiologic imaging techniques are insufficient to reliably detect lymph node metastases in prostate cancer. Despite promising results, there is limited published data on the diagnostic accuracy of PSMA PET-CT to assess local nodal metastases prior to radical prostatectomy. This study aims to assess the diagnostic efficacy of 68Ga PSMA PET-CT in local lymph node staging of high risk primary prostate cancer when compared to histopathological findings following radical prostatectomy with pelvic lymph node dissection.

Methods: We retrospectively analysed consecutive patients with high risk primary prostate cancer referred by urologists for primary staging PSMA PET-CT using a 68Ga-labeled PSMA ligand, Glu-NH-CO-NHLys-(Ahx)-[HBEDD-CC], from October 2015 to October 2017. The scans of patients who underwent radical prostatectomy with pelvic lymph node dissection were interpreted by the consensus reading of two experienced nuclear medicine physicians blinded to clinical and histopathological data. The contemporaneous records of the referring urologists were retrospectively reviewed for noteworthy unexpected PET findings that altered their personal preference for surgical management.

Results: Seventy-one patients were recruited and analysed. PSMA PET-CT showed findings compatible with local disease in 47 patients (66.2%), lymph node metastases in 10 patients (14.1%) and distant metastases in 14 patients (19.7%). Twenty-eight patients (twenty-seven of whom had local disease only) underwent surgery yielding 214 lymph nodes, all of which were negative on histopathological analysis. On a node-based analysis, 213 of 214 lymph nodes were accurately identified as negative for disease with a negative predictive value of 100%. 11 patients had unexpected PET findings contemporaneously documented by urologists to alter their preference for surgical management.

Conclusions: PSMA PET-CT appears to have a high negative predictive value for local lymph node metastases in high risk primary prostate cancer when compared to histopathological findings following radical prostatectomy with pelvic lymph node dissection.
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http://dx.doi.org/10.1186/s40644-019-0273-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907253PMC
December 2019

Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats.

Cells 2019 10 27;8(11). Epub 2019 Oct 27.

Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.

Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development.

Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction.

Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits.

Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.
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http://dx.doi.org/10.3390/cells8111326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912695PMC
October 2019

Expression-Based Cell Lineage Analysis in Through a Course-Based Research Experience for Early Undergraduates.

Authors:
John M Olson Cory J Evans Kathy T Ngo Hee Jong Kim Joseph Duy Nguyen Kayla G H Gurley Truc Ta Vijay Patel Lisa Han Khoa T Truong-N Letty Liang Maggie K Chu Hiu Lam Hannah G Ahn Abhik Kumar Banerjee In Young Choi Ross G Kelley Naseem Moridzadeh Awais M Khan Omair Khan Szuyao Lee Elizabeth B Johnson Annie Tigranyan Jay Wang Anand D Gandhi Manish M Padhiar Joseph Hargan Calvopina Kirandeep Sumra Kristy Ou Jessie C Wu Joseph N Dickan Sabrena M Ahmadi Donald N Allen Van Thanh Mai Saif Ansari George Yeh Earl Yoon Kimberly Gon John Y Yu Johnny He Jesse M Zaretsky Noemi E Lee Edward Kuoy Alexander N Patananan Daniel Sitz PhuongThao Tran Minh-Tu Do Samira J Akhave Silverio D Alvarez Bobby Asem Neda Asem Nicole A Azarian Arezou Babaesfahani Ahmad Bahrami Manjeet Bhamra Ragini Bhargava Rakesh Bhatia Subir Bhatia Nicholas Bumacod Jonathan J Caine Thomas A Caldwell Nicole A Calica Elise M Calonico Carman Chan Helen H-L Chan Albert Chang Chiaen Chang Daniel Chang Jennifer S Chang Nauman Charania Jasmine Y Chen Kevin Chen Lu Chen Yuyu Chen Derek J Cheung Jesse J Cheung Jessica J Chew Nicole B Chew Cheng-An Tony Chien Alana M Chin Chee Jia Chin Youngho Cho Man Ting Chou Ke-Huan K Chow Carolyn Chu Derrick M Chu Virginia Chu Katherine Chuang Arunit Singh Chugh Mark R Cubberly Michael Guillermo Daniel Sangita Datta Raj Dhaliwal Jenny Dinh Dhaval Dixit Emmylou Dowling Melinda Feng Christopher M From Daisuke Furukawa Himaja Gaddipati Lilit Gevorgyan Zunera Ghaznavi Tulika Ghosh Jaskaran Gill David J Groves Kalkidan K Gurara Ali R Haghighi Alexandra L Havard Nasser Heyrani Tanya Hioe Kirim Hong Justin J Houman Molly Howland Elaine L Hsia Justin Hsueh Stacy Hu Andrew J Huang Jasmine C Huynh Jenny Huynh Chris Iwuchukwu Michael J Jang An An Jiang Simran Kahlon Pei-Yun Kao Manpreet Kaur Matthew G Keehn Elizabeth J Kim Hannah Kim Michelle J Kim Shawn J Kim Aleksandar Kitich Ross A Kornberg Nicholas G Kouzelos Jane Kuon Bryan Lau Roger K Lau Rona Law Huy D Le Rachael Le Carrou Lee Christina Lee Grace E Lee Kenny Lee Michelle J Lee Regina V Lee Sean H K Lee Sung Kyu Lee Sung-Ling D Lee Yong Jun Lee Megan J Leong David M Li Hao Li Xingfu Liang Eric Lin Michelle M Lin Peter Lin Tiffany Lin Stacey Lu Serena S Luong Jessica S Ma Li Ma Justin N Maghen Sravya Mallam Shivtaj Mann Jason H Melehani Ryan C Miller Nitish Mittal Carmel M Moazez Susie Moon Rameen Moridzadeh Kaley Ngo Hanh H Nguyen Kambria Nguyen Thien H Nguyen Angela W Nieh Isabella Niu Seo-Kyung Oh Jessica R Ong Randi K Oyama Joseph Park Yaelim A Park Kimberly A Passmore Ami Patel Amy A Patel Dhruv Patel Tirth Patel Katherine E Peterson An Huynh Pham Steven V Pham Melissa E Phuphanich Neil D Poria Alexandra Pourzia Victoria Ragland Riki D Ranat Cameron M Rice David Roh Solomon Rojhani Lili Sadri Agafe Saguros Zainab Saifee Manjot Sandhu Brooke Scruggs Lisa M Scully Vanessa Shih Brian A Shin Tamir Sholklapper Harnek Singh Sumedha Singh Sondra L Snyder Katelyn F Sobotka Sae Ho Song Siddharth Sukumar Halley C Sullivan Mark Sy Hande Tan Sara K Taylor Shivani K Thaker Tulsi Thakore Gregory E Tong Jacinda N Tran Jonathan Tran Tuan D Tran Vivi Tran Cindy L Trang Hung G Trinh Peter Trinh Han-Ching H Tseng Ted T Uotani Akram V Uraizee Kent K T Vu Kevin K T Vu Komal Wadhwani Paluk K Walia Rebecca S Wang Shuo Wang Stephanie J Wang Danica D Wiredja Andrew L Wong Daniel Wu Xi Xue Griselda Yanez Yung-Hsuan Yang Zhong Ye Victor W Yee Cynthia Yeh Yue Zhao Xin Zheng Anke Ziegenbalg Jon Alkali Ida Azizkhanian Akash Bhakta Luke Berry Ryen Castillo Sonja Darwish Holly Dickinson Ritika Dutta Rahul Kumar Ghosh Riley Guerin Jonathan Hofman Garrick Iwamoto Sarah Kang Andrew Kim Brian Kim Hanwool Kim Kristine Kim Suji Kim Julie Ko Michael Koenig Alejandro LaRiviere Clifton Lee Jiwon Lee Brandon Lung Max Mittelman Mark Murata Yujin Park Daniel Rothberg Ben Sprung-Keyser Kunal Thaker Vivian Yip Paul Picard Francie Diep Nikki Villarasa Volker Hartenstein Casey Shapiro Marc Levis-Fitzgerald Leslie Jaworski David Loppato Ira E Clark Utpal Banerjee

G3 (Bethesda) 2019 11 5;9(11):3791-3800. Epub 2019 Nov 5.

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The AL4 echnique for eal-time nd lonal xpression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.
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http://dx.doi.org/10.1534/g3.119.400541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829132PMC
November 2019

New T1 classification.

Gen Thorac Cardiovasc Surg 2020 Jul 2;68(7):665-671. Epub 2019 Nov 2.

Department of Cardiothoracic Surgery, Queen Mary Hospital, Pok Fu Lam, Hong Kong.

The IASLC staging and Prognostic Factor Committee proposed new changes to the descriptors for the 8th edition of the Tumour Node Metastasis Staging for Lung Cancer. The T1 descriptor changes include (1) T1 tumours are subclassified into T1a (< 1 cm), T1b (> 1 to < 2 cm), T1c (> 2 to < 3 cm). The corresponding changes are introduced to the overall staging: T1aN0M0 = Stage IA1; T1bN0M0 = Stage IA2; T1cN0M0 = Stage IA3. (2) The introduction of the pathological entities Adenocarcinoma-In-Situ (AIS), Minimally Invasive Adenocarcinoma, and Lepidic Predominant Adenocarcinoma. The corresponding changes on the T descriptor are as follows: Adenocarcinoma-in situ is coded as Tis (AIS); Minimally Invasive Adenocarcinoma is coded as T1a(mi). In this review, the basis for these changes will be described, and the implications on clinical practice will be discussed.
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http://dx.doi.org/10.1007/s11748-019-01233-0DOI Listing
July 2020

PD-L1 aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients.

Cancer Lett 2020 01 31;469:355-366. Epub 2019 Oct 31.

Cytelligen, San Diego, CA, USA. Electronic address:

Sustained angiogenesis and increased PD-L1 expression on endothelial and carcinoma cells contribute toward fostering an immunosuppressive microenvironment suitable for tumor growth. PD-L1 CTCs were reported to associate with poor prognosis in NSCLC patients. However, whether or not aneuploid circulating tumor endothelial cells (CTECs) express PD-L1, then serve as a surrogate biomarker to evaluate immunotherapy efficacy remains unknown. In this study, a novel SE-iFISH strategy was established to comprehensively quantify and characterize a full spectrum of aneuploid CTCs and CTECs in advanced NSCLC patients subjected to second-line anti-PD-1 (nivolumab) immunotherapy. In situ co-detection of diverse subtypes of aneuploid CTCs and CTECs expressing PD-L1 and Vimentin was performed. The present clinical study demonstrated that significant amounts of PD-L1 aneuploid CTCs and CTECs could be detected in histopathologic hPD-L1 patients. In contrast to decreased PD-L1 CTCs, the number of multiploid PD-L1 CTECs (≥tetrasomy 8) undergoing post-therapeutic karyotype shifting increased in patients along with tumor progression following anti-PD-1 treatment. Progressive disease (PD) lung cancer patients possessing multiploid PD-L1 CTECs had a significantly shorter PFS compared to those without PD-L1 CTECs. In carcinoma patients, aneuploid CTCs and CTECs may exhibit a functional interplay with respect to tumor angiogenesis, progression, metastasis, and response to immunotherapy.
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http://dx.doi.org/10.1016/j.canlet.2019.10.041DOI Listing
January 2020