Publications by authors named "Peter Lee"

960 Publications

Study Protocol for a Global Survey: Awareness and Preparedness of Hospital Staff Against Coronavirus Disease (COVID-19) Outbreak.

Front Public Health 2021 1;9:580427. Epub 2021 Jul 1.

Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.

The outbreak of Coronavirus disease (COVID-19) caused by a novel coronavirus (named SARS-CoV-2) has gained attention globally and has been recognized as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) due to the rapidly increasing number of deaths and confirmed cases. Health care workers (HCWs) are vulnerable to this crisis as they are the first frontline to receive and manage COVID-19 patients. In this multicenter multinational survey, we aim to assess the level of awareness and preparedness of hospital staff regarding COVID-19 all over the world. From February to March 2020, the web-based or paper-based survey to gather information about the hospital staff's awareness and preparedness in the participants' countries will be carried out using a structured questionnaire based on the United States Centers for Disease Control and Prevention (CDC) checklist and delivered to participants by the local collaborators for each hospital. As of March 2020, we recruited 374 hospitals from 58 countries that could adhere to this protocol as approved by their Institutional Review Boards (IRB) or Ethics Committees (EC). The awareness and preparedness of HCWs against COVID-19 are of utmost importance not only to protect themselves from infection, but also to control the virus transmission in healthcare facilities and to manage the disease, especially in the context of manpower lacking and hospital overload during the pandemic. The results of this survey can be used to inform hospitals about the awareness and preparedness of their health staff regarding COVID-19, so appropriate policies and practice guidelines can be implemented to improve their capabilities of facing this crisis and other future pandemic-prone diseases.
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http://dx.doi.org/10.3389/fpubh.2021.580427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281218PMC
July 2021

Unconventional acoustic approaches for localized and designed micromanipulation.

Lab Chip 2021 Jul 16. Epub 2021 Jul 16.

Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia.

Acoustic fields are ideal for micromanipulation, being biocompatible and with force gradients approaching the scale of single cells. They have accordingly found use in a variety of microfluidic devices, including for microscale patterning, separation, and mixing. The bulk of work in acoustofluidics has been predicated on the formation of standing waves that form periodic nodal positions along which suspended particles and cells are aligned. An evolving range of applications, however, requires more targeted micromanipulation to create unique patterns and effects. To this end, recent work has made important advances in improving the flexibility with which acoustic fields can be applied, impressively demonstrating generating arbitrary arrangements of pressure fields, spatially localizing acoustic fields and selectively translating individual particles in ways that are not achievable via traditional approaches. In this critical review we categorize and examine these advances, each of which open the door to a wide range of applications in which single-cell fidelity and flexible micromanipulation are advantageous, including for tissue engineering, diagnostic devices, high-throughput sorting and microfabrication.
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http://dx.doi.org/10.1039/d1lc00378jDOI Listing
July 2021

Understanding Moral Injury and Belief Change in the Experiences of Police Online Child Sex Crime Investigators: an Interpretative Phenomenological Analysis.

J Police Crim Psychol 2021 Jun 30:1-13. Epub 2021 Jun 30.

Creative and Cultural Industries, University of Portsmouth, Portsmouth, UK.

Little is known about the psychological and physiological impacts of moral injury within organizational contexts such as Internet Child Abuse Teams (hereafter abbreviated to ICAT), who are repeatedly exposed to trauma through viewing and grading graphic images of children being sexually abused. The aims of the current research were to explore the key features of, and contributing factors to, moral injury and trauma as experienced by Internet Child Abuse Teams, how these manifested and how these factors can be mitigated. Six participants were recruited from ICATs located at two police constabularies. Data were gathered using semi-structured interviews and analysed using interpretative phenomenological analysis. Findings indicated that the moral injury experienced by the participants was predominantly attributable to repeated exposure to traumatising images, with too little decompression time. Dysfunctional coping mechanisms, most commonly substance misuse, cognitive avoidance of distressing thoughts and emotional numbing, amplified the psychological and physical symptoms of anxiety. For many ICAT investigators, such tactics were attempts to manage the moral violations arising from their work and experienced as moral injury. These findings will be used to inform psychological review systems and interventions within policing.
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http://dx.doi.org/10.1007/s11896-021-09463-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241533PMC
June 2021

Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer.

Eur J Cancer 2021 Jul 1;154:11-20. Epub 2021 Jul 1.

Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Beckman Research Institute, Duarte, CA, USA.

Background: CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR) human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC).

Patients And Methods: Women with stage IV HR HER2 MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy.

Results: Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33-70) and cohort 2 median age was 55 (37-75). Cohort 1 closed early due to limited accrual. Grade III-IV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete response (CR), 25% had PR and 31% had SD by Response Evaluation Criteria in Solid Tumours version 1.1. Median progression-free survival was 25.2 months (95% confidence interval [CI] 5.3, not reached) and median overall survival was 36.9 months (95% CI 36.9, not reached) in cohort 2 with a median follow-up of 24.8 months (95% CI 17.1, not reached). A correlative immune biomarker analysis was published separately.

Conclusion: The combination of palbociclib, pembrolizumab and letrozole is well tolerated, and a complete response rate of 31% was identified in HR MBC patients who received this combination as front-line therapy. Confirmatory trials are required to better understand the immune-priming effects of CDK4/6 inhibitors.
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http://dx.doi.org/10.1016/j.ejca.2021.05.035DOI Listing
July 2021

Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome.

NPJ Breast Cancer 2021 Jul 1;7(1):84. Epub 2021 Jul 1.

Department of Physics and Astronomy, University of California, Irvine, Irvine, CA, USA.

While tumor infiltration by CD8 T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method 'occupancy') to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.
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http://dx.doi.org/10.1038/s41523-021-00291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249408PMC
July 2021

Cigarette Filter Ventilation and Biomarkers-Letter.

Authors:
Peter Lee John Fry

Cancer Epidemiol Biomarkers Prev 2021 Jul;30(7):1449

Roelee Statistics Ltd, Sutton, Surrey, United Kingdom.

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http://dx.doi.org/10.1158/1055-9965.EPI-21-0122DOI Listing
July 2021

Ubiquitin-Conjugating Enzymes in Cancer.

Cells 2021 Jun 4;10(6). Epub 2021 Jun 4.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.
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http://dx.doi.org/10.3390/cells10061383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227520PMC
June 2021

Good Outcome for an Individual with Severe Facial Anomalies and Hypogonadotropic Hypogonadism: A Consequence of His Cognitive Function, Pragmatic Approach, and Temperament.

Case Rep Pediatr 2021 12;2021:9957218. Epub 2021 Jun 12.

Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.

The multiple factors that determine outcomes for individuals with visible developmental errors and/or atypical development of the reproductive system are not fully understood. This case report of an individual with Bosma arhinia microphthalmia syndrome causing severe facial anomalies and hypogonadotropic hypogonadism is used to highlight factors that impacted his adjustment from childhood through adulthood. Key factors include his temperament, intact cognitive ability, and pragmatic approach for controlling his physical and social environment. His successful adjustment even in the face of significant early life challenges demonstrates that positive outcomes are attainable for individuals with significant developmental errors. His story and experiences with the health-care system offer insight into some factors that may be pertinent to resilience and lifelong adjustment for patients with similar conditions and the importance of continually seeking the patient's perspective to tailor treatment across the lifespan.
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http://dx.doi.org/10.1155/2021/9957218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214474PMC
June 2021

Cardiac effects and clinical applications of MG53.

Cell Biosci 2021 Jun 28;11(1):115. Epub 2021 Jun 28.

Department of Surgery, The Ohio State University, Columbus, OH, USA.

Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.
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http://dx.doi.org/10.1186/s13578-021-00629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240287PMC
June 2021

Ecklonia cava fucoidan has potential to stimulate natural killer cells in vivo.

Int J Biol Macromol 2021 Jun 10;185:111-121. Epub 2021 Jun 10.

Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address:

Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.06.045DOI Listing
June 2021

Deep learning-based amyloid PET positivity classification model in the Alzheimer's disease continuum by using 2-[F]FDG PET.

EJNMMI Res 2021 Jun 10;11(1):56. Epub 2021 Jun 10.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Background: Considering the limited accessibility of amyloid position emission tomography (PET) in patients with dementia, we proposed a deep learning (DL)-based amyloid PET positivity classification model from PET images with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (2-[F]FDG).

Methods: We used 2-[F]FDG PET datasets from the Alzheimer's Disease Neuroimaging Initiative and Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease for model development. Moreover, we used an independent dataset from another hospital. A 2.5-D deep learning architecture was constructed using 291 submodules and three axes images as the input. We conducted the voxel-wise analysis to assess the regions with substantial differences in glucose metabolism between the amyloid PET-positive and PET-negative participants. This facilitated an understanding of the deep model classification. In addition, we compared these regions with the classification probability from the submodules.

Results: There were 686 out of 1433 (47.9%) and 50 out of 100 (50%) amyloid PET-positive participants in the training and internal validation datasets and the external validation datasets, respectively. With 50 times iterations of model training and validation, the model achieved an AUC of 0.811 (95% confidence interval (CI) of 0.803-0.819) and 0.798 (95% CI, 0.789-0.807) on the internal and external validation datasets, respectively. The area under the curve (AUC) was 0.860 when tested with the model with the highest value (0.864) on the external validation dataset. Moreover, it had 75.0% accuracy, 76.0% sensitivity, 74.0% specificity, and 75.0% F1-score. We found an overlap between the regions within the default mode network, thus generating high classification values.

Conclusion: The proposed model based on the 2-[F]FDG PET imaging data and a DL framework might successfully classify amyloid PET positivity in clinical practice, without performing amyloid PET, which have limited accessibility.
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http://dx.doi.org/10.1186/s13550-021-00798-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192639PMC
June 2021

High-throughput microfluidic compressibility cytometry using multi-tilted-angle surface acoustic wave.

Lab Chip 2021 07;21(14):2812-2824

Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC 3010, Australia.

Cellular mechanical properties (e.g. compressibility) are important biophysical markers in relation to cellular processes and functionality. Among the methods for cell mechanical measurement, acoustofluidic methods appear to be advantageous due to tunability, biocompatibility and acousto-mechanical nature. However, the previous acoustofluidic methods were limited in throughput and number of measurements. In this study, we developed a high-throughput microfluidic compressibility cytometry approach using multi-tilted-angle surface acoustic wave, which can provide thousands of single-cell compressibility measurements within minutes. The compressibility cytometer was constructed to drag microparticles or cells towards the microfluidic channel sidewall at different segments based on their biophysical properties (such as size and compressibility), as a result of the varied balance between acoustics and flow. Mathematical analysis and computational simulation revealed that the compressibility of a cell could be estimated from the position of collision with the sidewall. Microbeads of different materials and sizes were experimentally tested to validate the simulation and to demonstrate the capability to characterise size and compressibility. MDA MB231 cells, of the triple negative breast cancer subtype, were treated with the microtubule disrupting agent colchicine which increased compressibility and treated with the actin disrupting agent cytochalasin B which increased cell size but did not change compressibility. Moreover, the highly metastatic variant MDA MB231 LNm5 cell line showed increased compressibility compared to the parent MDA MB231 cells, indicating the potential utility of high-throughput mechanophenotyping for tumour cell characterisation.
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http://dx.doi.org/10.1039/d1lc00186hDOI Listing
July 2021

Comparative diagnostic accuracy of EUS needles in solid pancreatic masses: a network meta-analysis.

Endosc Int Open 2021 Jun 27;9(6):E853-E862. Epub 2021 May 27.

Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, United States.

Endoscopic ultrasound (EUS)-guided tissue sampling is the standard of care for diagnosing solid pancreatic lesions. While many two-way comparisons between needle types have been made in randomized controlled trials (RCTs), it is unclear which size and type of needle offers the best probability of diagnosis. We therefore performed a network meta-analysis (NMA) to compare different sized and shaped needles to rank the diagnostic performance of each needle. We searched MEDLINE, EMBASE and Cochrane Library databases through August, 2020 for RCTs that compared the diagnostic accuracy of EUS fine-needle aspiration (FNA) and biopsy (FNB) needles in solid pancreatic masses. Using a random-effects NMA under the frequentist framework, RCTs were analyzed to identify the best needle type and sampling technique. Performance scores (P-scores) were used to rank the different needles based on pooled diagnostic accuracy. The NMA model was used to calculate pairwise relative risk (RR) with 95 % confidence intervals. Review of 2577 studies yielded 29 RCTs for quantitative synthesis, comparing 13 different needle types. All 22G FNB needles had an RR > 1 compared to the reference 22G FNA (Cook) needle. The highest P-scores were seen with the 22G Medtronic FNB needle (0.9279), followed by the 22G Olympus FNB needle (0.8962) and the 22G Boston Scientific FNB needle (0.8739). Diagnostic accuracy was not significantly different between needles with or without suction. In comparison to FNA needles, FNB needles offer the highest diagnostic performance in sampling pancreatic masses, particularly with 22G FNB needles.
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http://dx.doi.org/10.1055/a-1381-7301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159621PMC
June 2021

Factors Associated with Mutations: Their Matching Rates to Cardiovascular and Neurological Diseases.

Int J Mol Sci 2021 May 11;22(10). Epub 2021 May 11.

Department of Biomedical Engineering, College of Engineering and Computer Sciences, Marshall University, Huntington, WV 25755, USA.

Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving >25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as we checked the two factors in genes associated with essential hypertension (EH), thoracic aortic aneurysm (TAA), and congenital heart disease (CHD), resulting in matching rates of 53%, 70%, and 75%, respectively. A matching of telomere proximity or high adenine and thymine content projects the list of loci involving rare mutations of monogenic hypertension better than those of other CVDs, likely due to adoption of rigorous criteria for true-positive signals. Our data suggest that the factor-disease matching rate is an accurate tool that can explain deleterious mutations of monogenic hypertension at a >80% match-unlike the relatively lower matching rates found in human genes of EH, TAA, CHD, and familial Parkinson's disease.
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http://dx.doi.org/10.3390/ijms22105057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151074PMC
May 2021

Progress on In Situ and Operando X-ray Imaging of Solidification Processes.

Materials (Basel) 2021 May 2;14(9). Epub 2021 May 2.

Department of Mechanical Engineering, University College London, London WC1E 7JE, UK.

In this review, we present an overview of significant developments in the field of in situ and operando (ISO) X-ray imaging of solidification processes. The objective of this review is to emphasize the key challenges in developing and performing in situ X-ray imaging of solidification processes, as well as to highlight important contributions that have significantly advanced the understanding of various mechanisms pertaining to microstructural evolution, defects, and semi-solid deformation of metallic alloy systems. Likewise, some of the process modifications such as electromagnetic and ultra-sound melt treatments have also been described. Finally, a discussion on the recent breakthroughs in the emerging technology of additive manufacturing, and the challenges thereof, are presented.
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http://dx.doi.org/10.3390/ma14092374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125014PMC
May 2021

Use of gonadotropin-releasing hormone analogs in children.

Curr Opin Pediatr 2021 08;33(4):442-448

Division of Endocrinology and Diabetes, Department of Pediatrics, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.

Purpose Of Review: In this review, we outline the usage and formulations of gonadotropin-releasing hormone analogs (GnRHas) in central precocious puberty (CPP), short stature, and gender diverse individuals, as well as adverse effects, long-term outcomes, and monitoring of therapy. There is a particular focus on citing references published within the last 24 months.

Recent Findings: Long-acting formulations of GnRHa now include Federal Drug Administration approval for subcutaneous injections. Significant adverse events continue to be rarely reported; extremely rare events include arterial hypertension and pseudotumor cerebri. There continue to be no significant long-term consequences including the impact upon body mass index and bone mineral density, which appear to be transient. GnRHas have been used in differences of sexual development (DSD) and increasingly in the treatment of adolescent transgender individuals.

Summary: GnRHas remain as the only fully efficacious therapy for CPP and effectively suppress pubertal hormones in other situations. The use of GnRHa therapy in gender incongruent individuals has proven beneficial and has become a standard of care, whereas use in those with DSDs should still be considered experimental.

Video Abstract: http://links.lww.com/MOP/A62.
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http://dx.doi.org/10.1097/MOP.0000000000001026DOI Listing
August 2021

Astragalus membranaceus polysaccharides potentiate the growth-inhibitory activity of immune checkpoint inhibitors against pulmonary metastatic melanoma in mice.

Int J Biol Macromol 2021 Jul 14;182:1292-1300. Epub 2021 May 14.

Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai 201508, China; Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address:

Astragalus membranaceus (A. membranaceus) is commonly used in various herbal formulations to treat several human and animal diseases. Polysaccharides, which are the major bioactive components in the A. membranaceus, exhibit various bioactive properties. However, the ability of A. membranaceus polysaccharides (APS) to activate the mucosal immune response has not been examined. We examined the effect of intranasal administration of APS on mucosal immune cell activation and the growth-inhibitory activity against pulmonary metastatic melanoma in mice by combination treatment with immune checkpoint blockade. The intranasal treatment of APS increased the number of lineageCD11c dendritic cell (DCs) in the mesenteric lymph nodes (mLN) through the upregulation of CC-chemokine receptor 7 expression. Moreover, intranasal treatment of APS activated DCs, which further stimulated natural killer (NK) and T cells in the mLN. The APS/anti-PD-L1 antibody combination inhibited the pulmonary infiltration of B16 melanoma cells. The depletion of NK cells and CD8 T cells in mice mitigated the anti-cancer effect of this combination, thereby highlighting the critical role of NK cells and CD8 T cells in mediating anti-cancer immunity. These findings demonstrated that APS could be used as a topical mucosal adjuvant to enhance the immune check point inhibitor anti-cancer effect.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.05.073DOI Listing
July 2021

A Novel 5-Cytokine Panel Outperforms Conventional Predictive Markers of Persistent Organ Failure in Acute Pancreatitis.

Clin Transl Gastroenterol 2021 May 6;12(5):e00351. Epub 2021 May 6.

Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Introduction: Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort.

Methods: The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010. Twenty-five cytokines associated with an acute inflammatory response were ranked by computing the mutual information between their levels and the outcome of POF; 5 high-ranking cytokines were selected. These cytokines were subsequently measured in early serum samples of an independent prospective verification cohort of 133 patients (2012-2016), and the results were trained in a Random Forest classifier. Cross-validated performance metrics were compared with the predictive accuracies of conventional laboratory tests and clinical scores.

Results: Angiopoietin 2, hepatocyte growth factor, interleukin 8, resistin, and soluble tumor necrosis factor receptor 1A were the highest-ranking cytokines in the derivation cohort; each reflects a pathologic process relevant to POF. A Random Forest classifier trained the cytokine panel in the verification cohort and achieved a 10-fold cross-validated accuracy of 0.89 (area under the curve 0.91, positive predictive value 0.89, and negative predictive value 0.90), which outperformed individual cytokines, laboratory tests, and clinical scores (all P ≤ 0.006).

Discussion: We developed a 5-cytokine panel, which accurately predicts POF early in the disease process and significantly outperforms the prognostic accuracy of existing laboratory tests and clinical scores.
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http://dx.doi.org/10.14309/ctg.0000000000000351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104185PMC
May 2021

Observation of microstructure evolution during inertia friction welding using in-situ synchrotron X-ray diffraction.

J Synchrotron Radiat 2021 May 19;28(Pt 3):790-803. Epub 2021 Mar 19.

Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, United Kingdom.

The widespread use and development of inertia friction welding is currently restricted by an incomplete understanding of the deformation mechanisms and microstructure evolution during the process. Understanding phase transformations and lattice strains during inertia friction welding is essential for the development of robust numerical models capable of determining optimized process parameters and reducing the requirement for costly experimental trials. A unique compact rig has been designed and used in-situ with a high-speed synchrotron X-ray diffraction instrument to investigate the microstructure evolution during inertia friction welding of a high-carbon steel (BS1407). At the contact interface, the transformation from ferrite to austenite was captured in great detail, allowing for analysis of the phase fractions during the process. Measurement of the thermal response of the weld reveals that the transformation to austenite occurs 230 °C below the equilibrium start temperature of 725 °C. It is concluded that the localization of large strains around the contact interface produced as the specimens deform assists this non-equilibrium phase transformation.
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http://dx.doi.org/10.1107/S1600577521001569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127373PMC
May 2021

A sono-anatomical and cadaveric study of ultrasound-guided retrolaminar block.

Med Ultrason 2021 Apr 22. Epub 2021 Apr 22.

Department of Anaesthesia Cork University Hospital Cork, Ireland.

Aim: Retrolaminar block (RB) is known to confer chest wall analgesia but, its mechanism has not been established. Our primary objective was to determine if the spread of injectate following RB extends to the paravertebral space (PVS). Second-ary objectives were to determine the predefined anatomical areas and nervous tissues contacted by injectate; the effect of volume on spread; and the extent to which experts can predict PVS spread based on examination of US videos of the injection.

Material And Methods: US-guided RB was performed on cadavers using a single injection technique of 10, 20 or 30 ml dye. Anatomical dissection was performed to identify the extent of spread of injectate to the retrolaminar, intercostal and PVS. Ultrasound recordings of the injection were independently evaluated by experts in US-guided regional anaesthesia.

Results: Spread of injectate to the ipsilateral PVS was identified in 6/10 dissected regions (0/1, 1/3 and 5/6 when injectate volumes of 10, 20 and 30ml were administered respectively). The extent of cephalad-caudad spread within the PVS varied from 1 to 3 levels. Expert interpretation of ultrasound images regarding spread to the PVS demonstrated poor correlation with dye staining observed on dissection.

Conclusions: Injectate spread following RB demonstrated substantial variability. Inconsistent spread to the ipsilateral PVS may account for clinically occurring incomplete blocks. The likelihood of spread to the ipsilateral PVS was greater when a larger volume was injected. Expert evaluation of the dynamic ultrasound images obtained at injection can-not reliably predict spread to the PVS.
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http://dx.doi.org/10.11152/mu-2979DOI Listing
April 2021

EUS and secretin endoscopic pancreatic function test predict evolution to overt structural changes of chronic pancreatitis in patients with nondiagnostic baseline imaging.

Endosc Ultrasound 2021 Mar-Apr;10(2):116-123

Department of Gastroenterology, Digestive Disease Institute, The Cleveland Clinic, Cleveland, OH, USA.

Background And Objectives: The accuracy of EUS and endoscopic pancreatic function test (ePFT) for diagnosis of early or minimal-change chronic pancreatitis (MCCP) is poorly understood. We hypothesized that the natural history of the disease may be used as a "gold standard" to assess the ability of EUS and ePFT to predict the eventual development of overt chronic pancreatitis (CP) changes on computed tomography/magnetic resonance cholangiopancreatography (CT/MRCP). The aim of the study was to determine the ability of EUS and ePFT to predict disease progression in patients with suspected MCCP who had nondiagnostic baseline imaging.

Methods: A retrospective cohort study was conducted. Patients who underwent EUS and ePFT for suspected CP and who had nondiagnostic CT or MRCP were included. Patients without repeat imaging performed more than 1 year after their initial EUS/ePFT were excluded. Imaging was considered diagnostic if calcifications, main duct dilation (Cambridge Class III/IV), or severe atrophy were identified. Patients lost to follow-up were contacted to complete a survey documenting current symptoms and whether patients progressed to CP based on imaging. Univariable and multivariable analyses were performed using Cox regression.

Results: Two hundred and thirty patients who underwent EUS/ePFT for suspected MCCP were identified between 2006 and 2012. Of these, 90 had a non-diagnostic baseline imaging test and subsequently a follow-up imaging test greater than 1 year later. These 90 patients constituted our study population. During a mean follow-up of 7 years, 19 (21%) patients developed CP by histology and imaging. Abnormal ePFT (peak bicarbonate <80 mmol) was a significant predictor of progression (hazard ratio [HR]: 4.7, confidence interval [CI]: 1.8, 12.4). Likewise, EUS Rosemont classification "suggestive/most-consistent" was a significant predictor of progression (HR: 7.3, CI: 2.4, 22.1).

Conclusions: In patients with abdominal pain of suspected pancreatic origin and with nondiagnostic cross-sectional imaging, EUS and ePFT results predict the development of classic CP structural changes over time. These results support EUS and ePFT as effective tools for predicting progression of minimal change to overt CP.
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http://dx.doi.org/10.4103/EUS-D-20-00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098843PMC
April 2021

Biomechanical and cognitive interactions during Visuo Motor Targeting Task.

Gait Posture 2021 05 26;86:287-291. Epub 2021 Mar 26.

Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

Background: Biomechanical analyses primarily focus on physical aspects of human movement; however, it is not understood how walking is affected while simultaneously performing a demanding cognitive task - a form of Cognitive-Motor Interference (CMI). CMI occurs when performance of a primary task (e.g. walking) is affected following the introduction of a cognitive task (e.g. visual search).

Research Question: Would Visuo Motor Targeting Task (VMTT) impair visual search performance and reduce the margin of stability (MoS) at higher gait speeds?

Methods: A protocol was developed to investigate responses of the neuromuscular system while performing a complex visual search task. The Computer Assisted Rehabilitation ENvironment (CAREN, Motekforce Link, Netherlands) system was used for the experimental design. Twenty male participants (Age = 24.2 ± 2.5yrs, Weight = 70.3 ± 10.6 kg, Height = 178.0 ± 9.1 cm) located and pointed towards targets in complex scenes while walking at different gait speeds (0.55, 1.11 and 1.67 m/s.) or while stationary. The cost of visual search during a Visuo Motor Targeting Task (VMTT) was based on the pointing accuracy during the visual search task.

Results: A two-way repeated measure ANOVA showed that MoS in the ML direction significantly improved with increased gait speed and during the visual search task. There was also a significant interaction with MoS improvement being greater during the visual search task at high gait speeds. MoS in the AP was only affected by gait speed. Visual performance and cost of visual search were enhanced during walking versus standing up to 25 %.

Significance: This study investigated CMI at different gait speeds, which may have implications in postural control, falls and other neurological disorders.
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http://dx.doi.org/10.1016/j.gaitpost.2021.03.030DOI Listing
May 2021

3D printed silica-gelatin hybrid scaffolds of specific channel sizes promote collagen Type II, Sox9 and Aggrecan production from chondrocytes.

Mater Sci Eng C Mater Biol Appl 2021 Apr 12;123:111964. Epub 2021 Feb 12.

Department of Materials, Imperial College London, London SW7 2AZ, UK. Electronic address:

Inorganic/organic hybrids have co-networks of inorganic and organic components, with the aim of obtaining synergy of the properties of those components. Here, a silica-gelatin sol-gel hybrid "ink" was directly 3D printed to produce 3D grid-like scaffolds, using a coupling agent, 3-glycidyloxypropyl)trimethoxysilane (GPTMS), to form covalent bonds between the silicate and gelatin co-networks. Scaffolds were printed with 1 mm strut separation, but the drying method affected the final architecture and properties. Freeze drying produced <40 μm struts and large ~700 μm channels. Critical point drying enabled strut consolidation, with ~160 μm struts and ~200 μm channels, which improved mechanical properties. This architecture was critical to cellular response: when chondrocytes were seeded on the scaffolds with 200 μm wide pore channels in vitro, collagen Type II matrix was preferentially produced (negligible amount of Type I or X were observed), indicative of hyaline-like cartilaginous matrix formation, but when pore channels were 700 μm wide, Type I collagen was prevalent. This was supported by Sox9 and Aggrecan expression. The scaffolds have potential for regeneration of articular cartilage regeneration, particularly in sports medicine cases.
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http://dx.doi.org/10.1016/j.msec.2021.111964DOI Listing
April 2021

Pelvic exenteration: Pre-, intra-, and post-operative considerations.

Surg Oncol 2021 Jun 19;37:101546. Epub 2021 Mar 19.

Royal Prince Alfred Hospital, Department of Colorectal Surgery, Sydney, Australia; Surgical Outcomes Research Centre, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

This review outlines the role of pelvic exenteration (PE) in the management of certain locally-advanced primary and recurrent rectal cancers. PE has undergone significant evolution over the past decades. Advances in pre-, intra-, and post-operative care have been directed towards achieving the 'holy grail' of an R0 resection, which remains the most important predictor of survival, quality of life, morbidity, and cost effectiveness following PE. Patient selection for surgery is largely determined by assessment of resectability. Pelvic magnetic resonance imaging determines the extent of local disease, while positron emission tomography remains the most accurate tool for exclusion of distant metastases. PE in the setting of metastatic disease or with palliative intent remains controversial. The intra-operative approach is based on the anatomical division of the pelvis into five compartments (anterior, central, posterior, and two lateral). Within each compartment are various possible dissection planes which are elected depending on the extent of tumour involvement. Innovations in surgical technique have allowed 'higher and wider' dissection planes with resultant en bloc excision of major vessels, major nerves, and bone. Evidence of improved R0 resection and survival rates with these techniques justifies the radicality of these novel approaches. Post-operative care for PE patients is technically demanding with a substantial hospital resource burden. Unique considerations for PE patients include the 'empty pelvis syndrome', urological complications, and management of post-operative malnutrition. While undeniably a morbid procedure, quality of life largely returns to baseline at six months, and for long-term survivors is sustained for up to five years.
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http://dx.doi.org/10.1016/j.suronc.2021.101546DOI Listing
June 2021

Specimen-specific fracture risk curves of lumbar vertebrae under dynamic axial compression.

J Mech Behav Biomed Mater 2021 06 16;118:104457. Epub 2021 Mar 16.

Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Underbody blast attacks of military vehicles by improvised explosives have resulted in high incidence of lumbar spine fractures below the thorocolumbar junction in military combatants. Fracture risk curves related to vertical loading at individual lumbar spinal levels can be used to assess the protective ability of new injury mitigation equipment. The objectives of this study were to derive fracture risk curves for the lumbar spine under high rate compression and identify how specimen-specific attributes and lumbar spinal level may influence fracture risk. In this study, we tested a sample of three-vertebra specimens encompassing all spinal levels between T12 to S1 in high-rate axial compression. Each specimen was tested with a non-injurious load, followed by a compressive force sufficient to induce vertebral body fracture. During testing, bone fracture was identified using measurements from acoustic emission sensors and changes in load cell readings. Following testing, the fractures were assessed using computed tomographic (CT) imaging. The CT images showed isolated fractures of trabecular bone, or fractures involving both cortical and trabecular bone. Results from the compressive force measurements in conjunction with a survival analysis demonstrated that the compressive force corresponding to fracture increased inferiorly as a function of lumbar spinal level. The axial rigidity (EA) measured at the mid-plane of the centre vertebra or the volumetric bone mineral density (vBMD) of the vertebral body trabecular bone most greatly influenced fracture risk. By including these covariates in the fracture risk curves, no other variables significantly affected fracture risk, including the lumbar spinal level. The fracture risk curves presented in this study may be used to assess the risk of injury at individual lumbar vertebra when exposed to dynamic axial compression.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104457DOI Listing
June 2021

Modulated Start-Up Mode of Cancer Cell Migration Through Spinophilin-Tubular Networks.

Front Cell Dev Biol 2021 9;9:652791. Epub 2021 Mar 9.

Department of Physiology, College of Medicine, Gachon University, Incheon, South Korea.

Spinophilin (SPL) is a multifunctional actin-binding scaffolding protein. Although increased research on SPL in cancer biology has revealed a tumor suppressive role, its modulation in cancer biology, and oncological relevance remains elusive. Thus, we determined the role of SPL in the modulation of the junctional network and cellular migration in A549 lung cancer cell line. Knockdown of SPL promoted cancer cell invasion in agarose spot and scratch wound assays. Attenuation of SPL expression also enhanced invadopodia, as revealed by enhanced vinculin spots, and enhanced sodium bicarbonate cotransporter NBC activity without enhancing membranous expression of NBCn1. Disruption of the tubular structure with nocodazole treatment revealed enhanced SPL expression and reduced NBC activity and A549 migration. SPL-mediated junctional modulation and tubular stability affected bicarbonate transporter activity in A549 cells. The junctional modulatory function of SPL in start-up migration, such as remodeling of tight junctions, enhanced invadopodia, and increased NBC activity, revealed here would support fundamental research and the development of an initial target against lung cancer cell migration.
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http://dx.doi.org/10.3389/fcell.2021.652791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985070PMC
March 2021

Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer.

J Immunother Cancer 2021 Mar;9(3)

Medical Oncology, City of Hope National Medical Center, Duarte, California, USA

Background: Single-agent pembrolizumab treatment of hormone receptor-positive metastatic breast cancer (MBC) has demonstrated modest clinical responses. Little is known about potential biomarkers or mechanisms of response to immune checkpoint inhibitors (ICIs) in patients with HR+ MBC. The present study presents novel immune correlates of clinical responses to combined treatment with CDK4/6i and ICI.

Methods: A combined analysis of two independent phase I clinical trials treating patients with HR+ MBC was performed. Patients treated with the combination of the CDK4/6i palbociclib+the ICI pembrolizumab+the aromatase inhibitor (AI) letrozole (palbo+pembro+AI) were compared with patients treated with pembrolizumab+AI (pembro+AI). Peripheral blood mononuclear cells collected at pretreatment, 3 weeks (cycle 2 day 1) and 9 weeks (cycle 4 day 1) were characterized by high-parameter flow cytometry to assess baseline immune subset composition and longitudinal changes in response to therapy.

Results: In the peripheral blood, higher pretreatment frequencies of effector memory CD45RA CD8 T cells and effector memory CD4 T cells were observed in responders to palbo+pembro+AI. In contrast, this was not observed in pembro+AI-treated patients. We further characterized T-cell subsets of effector-like killer cell lectin-like receptor subfamily G member 1 (KLRG1) ICOS CD4 T cells and KLRG1 CD45RA CD8 T cells as baseline biomarkers of response. In comparison, pretreatment levels of tumor-infiltrating lymphocyte, tumor mutation burden, tumor programmed death-ligand 1 expression, and overall immune composition did not associate with clinical responses. Over the course of treatment, significant shifts in myeloid cell composition and phenotype were observed in palbo+pembro+AI-treated patients, but not in those treated with pembro+AI. We identified increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib. We also demonstrated that in palbociclib-treated patients, cDC1 and cMO displayed increased CD83 and human leukocyte antigen-DR isotype (HLA-DR) expression, respectively, suggesting increased maturation and antigen presentation capacity.

Conclusions: Pre-existing circulating effector CD8 and CD4 T cells and dynamic modulation of circulating myeloid cell composition denote response to combined pembrolizumab and palbociclib therapy for patients with HR+ MBC.

Trial Registration Number: NCT02778685 and NCI02648477.
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http://dx.doi.org/10.1136/jitc-2020-002084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993344PMC
March 2021

Elderly Patients Have Better Quality of Life but Worse Survival Following Pelvic Exenteration: A 25-Year Single-Center Experience.

Ann Surg Oncol 2021 Mar 9. Epub 2021 Mar 9.

Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Objective: To describe quality of life (QOL) and survival outcomes following pelvic exenteration (PE) in old and young patients.

Background: PE is a management option for complete resection in locally advanced pelvic cancers. Few studies have examined the impact of age on the outcome in elderly patients following PE.

Patients And Methods: Prospective cohort of consecutive patients undergoing partial and complete PE between 1994 and 2019. Patients were divided into a younger (< 65 years) or older cohort (≥ 65 years) based on their age. QoL was assessed using the SF-36 and FACT-C questionnaires and survival estimated using the Kaplan-Meier method.

Results: For 710 patients who underwent PE during the study period, FACT-C total score was significantly better in the elderly during the whole follow-up period of 5 years. Mental component score (SF-36) was significantly better at baseline (p = 0.008) and at 24 months postoperatively (p = 0.042), in the elderly group. Median overall survival was 75 months in the younger cohort and 53 months in the older cohort (p = 0.004). In subgroup analysis, older patients with recurrent or primary rectal cancer had a median survival of 37 and 70 months, respectively. Postoperative cardiovascular complications were greater in the elderly cohort (p < 0.001).

Conclusions: Elderly patients had better overall QoL but lower survival that is probably related to cardiovascular complications rather than to cancer as both groups had similar R0 resection rate. Hence, the elderly population should be considered equally for PE.
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http://dx.doi.org/10.1245/s10434-021-09685-6DOI Listing
March 2021