bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the Lowest Threshold of Vascular Benefits from LDL Cholesterol Lowering with a PCSK9 mAb Inhibitor (Alirocumab) in Patients with Stable Cardiovascular Disease (INTENSITY-HIGH): protocol and study rationale for a randomised, open label, parallel group, mechanistic study
Authors: Cacciottolo Paul J , Kostapanos Michalis S , Hernan Sancho Elena , Pavey Holly , Kaloyirou Fotini , Vamvaka Evangelia , Helmy Joanna , Hubsch Annette , McEniery Carmel M , Wilkinson Ian B , Cheriyan Joseph
Published: April 2021

Introduction

Elevated low-density lipoprotein cholesterol (LDL-C) is a strong independent risk predictor of cardiovascular (CV) events, while interventions to reduce it remain the only evidence-based approach to reduce CV morbidity and mortality. Secondary prevention statin trials in combination with ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors showed that there is no ‘J shaped curve’ in LDL-C levels with regard to CV outcomes. The lowest threshold beyond which reduction of LDL-C confers no further CV benefits has not been identified.

The INTENSITY-HIGH study seeks to explore physiological mechanisms mediating CV benefits of LDL-C lowering by PCSK9 inhibition in patients with established cardiovascular disease (CVD). The study examines the changes in measures of endothelial function and vascular inflammation imaging following intervention with PCSK9 and against standard of care.

Methods and analysis

This is a single-centre, randomised, open label, parallel group, mechanistic physiological study. It will include approximately 60 subjects with established CVD, with LDL-C of <4.1 mmol/L on high-intensity statins. All eligible participants will undergo 18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) scanning of the aorta and carotid arteries, as well as baseline endothelial function assessment. Subsequently, they will be randomised on a 1:1 basis to either alirocumab 150 mg or ezetimibe 10 mg/day. Repeat FDG-PET/CT scan and vascular assessments will be undertaken after 8 weeks of treatment. Any changes in these parameters will be correlated with changes in lipid levels and systemic inflammation biomarkers.

Ethics and dissemination

The study received a favourable opinion from the Wales Research Ethics Committee 4, was registered on clinicaltrials.gov and conformed to International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice. The results of this study will be reported through peer-reviewed journals and conference presentations.

Trial registration number

NCT03355027.
Qualitative analysis of stakeholder interviews to identify the barriers and facilitators to the adoption of point-of-care diagnostic tests in the UK
Authors: Huddy Jeremy R , Ni Melody Zhifang , Barlow James , Hanna George B
Published: April 2021

Objectives

This study investigated the barriers and facilitators to the adoption of point-of-care tests (POCTs).

Design

Qualitative study incorporating a constant comparative analysis of stakeholder responses to a series of interviews undertaken to design the Point-of-Care Key Evidence Tool.

Setting

The study was conducted in relation to POCTs used in all aspects of healthcare.

Participants

Forty-three stakeholders were interviewed including clinicians (incorporating laboratory staff and members of trust POCT committees), commissioners, industry, regulators and patients.

Results

Thematic analysis highlighted 32 barriers in six themes and 28 facilitators in eight themes to the adoption of POCTs. Six themes were common to both barriers and facilitators (clinical, cultural, evidence, design and quality assurance, financial and organisational) and two themes contained facilitators alone (patient factors and other (non-financial) resource use).

Conclusions

Findings from this study demonstrate the complex motivations of stakeholders in the adoption of POCT. Most themes were common to both barriers and facilitators suggesting that good device design, stakeholder engagement and appropriate evidence provision can increase the likelihood of a POCT device adoption. However, it is important to realise that while the majority of identified barriers may be perceived or mitigated some may be absolute and if identified early in device development further investment should be carefully considered.
Prevalence and factors associated with depression, anxiety and stress among healthcare workers of Trinidad and Tobago during COVID-19 pandemic: a cross-sectional study
Authors: Nayak B Shivananda , Sahu Pradeep Kumar , Ramsaroop Koomatie , Maharaj Shivanand , Mootoo William , Khan Sharaz , Extavour Rian Marie
Published: April 2021

Objectives

To determine the prevalence and factors associated with depression, anxiety and stress among healthcare workers (HCWs) during COVID-19 pandemic.

Design

Cross-sectional online survey.

Setting

HCWs from four major hospitals within the Regional Health Authorities of Trinidad and Tobago.

Participants

395 HCWs aged ≥18 years.

Main outcome measures

Depression, anxiety and stress scores.

Results

Among the 395 HCWs, 42.28%, 56.2% and 17.97% were found to have depression, anxiety and stress, respectively. In the final stepwise regression model, contact with patients with confirmed COVID-19, p<0.001 (95% CI 3.072 to 6.781) was reported as significant predictors of depression. Further, gender, p<0.001 (95% CI 2.152 to 5.427) and marital status, p<0.001 (95% CI 1.322 to 4.270) of the HCWs were considered to be correlated with anxiety. HCWs who had contact with patients with suspected COVID-19 had lower depression, p<0.001 (95% CI −5.233 to −1.692) and stress, p<0.001 (95% CI −5.364 to −1.591).

Conclusions

This study has depicted the prevalence and evidence of depression, anxiety and stress among HCWs during the COVID-19 pandemic. The findings of the study will serve as supportive evidence for the timely implementation of further planning of preventative mental health services by the Ministry of Health, for frontline workers within the public and private health sectors.
Hemogram as Marker of In-Hospital Mortality in Covid-19
Authors: López-Escobar Alejandro , Madurga Rodrigo , Castellano José María , Ruiz de Aguiar Santiago , Velázquez Sara , Bucar Marina , Jimeno Sara , Ventura Paula Sol
Published: April 2021

The clinical impact of COVID-19 disease calls for the identification of routine variables to identify patients at increased risk of death. Current understanding of moderate-to-severe COVID-19 pathophysiology points toward an underlying cytokine release driving a hyperinflammatory and procoagulant state. In this scenario, white blood cells and platelets play a direct role as effectors of such inflammation and thrombotic response. We investigate whether hemogram-derived ratios such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and the systemic immune-inflammation index may help to identify patients at risk of fatal outcomes. Activated platelets and neutrophils may be playing a decisive role during the thromboinflammatory phase of COVID-19 so, in addition, we introduce and validate a novel marker, the neutrophil-to-platelet ratio (NPR).

Two thousand and eighty-eight hospitalized patients with COVID-19 admitted at any of the hospitals of HM Hospitales group in Spain, from March 1 to June 10, 2020, were categorized according to the primary outcome of in-hospital death.

Baseline values, as well as the rate of increase of the four ratios analyzed were significantly higher at hospital admission in patients who died than in those who were discharged (p<0.0001). In multivariable logistic regression models, NLR (OR 1.05; 95% CI 1.02 to 1.08, p=0.00035) and NPR (OR 1.23; 95% CI 1.12 to 1.36, p<0.0001) were significantly and independently associated with in-hospital mortality.

According to our results, hemogram-derived ratios obtained at hospital admission, as well as the rate of change during hospitalization, may easily detect, primarily using NLR and the novel NPR, patients with COVID-19 at high risk of in-hospital mortality.
CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation
Authors: Reyes Ryan Michael , Deng Yilun , Zhang Deyi , Ji Niannian , Mukherjee Neelam , Wheeler Karen , Gupta Harshita B , Padron Alvaro S , Kancharla Aravind , Zhang Chenghao , Garcia Myrna , Kornepati Anand V R , Boyman Onur , Conejo-Garcia Jose R , Svatek Robert S , Curiel Tyler J
Published: April 2021

Background

Anti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.

Methods

We studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.

Results

IL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+T cells but not γδ T cells.

Conclusions

Mechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.
Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study
Authors: Lee Meghan D , Seethapathy Harish , Strohbehn Ian A , Zhao Sophia H , Boland Genevieve M , Fadden Riley , Sullivan Ryan , Reynolds Kerry L , Sise Meghan E
Published: April 2021

Background

Current guidelines for treatment of immune checkpoint inhibitor (ICI)-induced nephritis are not evidence based and may lead to excess corticosteroid exposure. We aimed to compare a rapid corticosteroid taper to standard of care.

Methods

Retrospective cohort study in patients with ICI-induced nephritis comparing a rapid taper beginning with 60 mg/day prednisone and tapered to 10 mg within 3 weeks to a historical control group that began 60 mg/day tapered to 10 mg within 6 weeks (standard of care). Renal recovery was defined as creatinine returning to within 1.5-fold baseline. The log-rank test compared the differences in time to renal recovery between the groups. We report rates of renal recovery at 30, 60 and 90 days, and timing and outcomes of ICI rechallenge.

Results

Thirteen patients received rapid corticosteroid taper and 14 patients received standard of care. Baseline characteristics were similar between groups. The median time to ≤10 mg/day prednisone was 20 days (IQR 15–25) in the rapid-taper group compared with 38 days (IQR 30–58) in the standard-of-care group. There was no significant difference in the time to renal recovery between the groups, though numerically higher numbers of patients recovered by 30 days, 11 (85%) in the rapid-taper arm versus 6 (46%) in the standard of care arm. Exposure to other nephritis-causing medications (proton pump inhibitor or trimethoprim-sulfamethoxazole) during the corticosteroid taper was more common in the standard of care group, 9 (64%) versus rapid-taper group, 2 (15%), and was associated with longer time to renal recovery, 20 days (IQR 14–101) versus 13 days (IQR 7–34) in those that discontinued nephritis-causing medications. Fifteen (56%) of patients were rechallenged with ICIs, and only two (13%) developed recurrent nephritis.

Conclusions

Patients with ICI-induced nephritis have excellent kidney outcomes when treated with corticosteroids that are tapered over 3 weeks.
Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors
Authors: Fucà Giovanni , Corti Francesca , Ambrosini Margherita , Intini Rossana , Salati Massimiliano , Fenocchio Elisabetta , Manca Paolo , Manai Chiara , Daniel Francesca , Raimondi Alessandra , Morano Federica , Corallo Salvatore , Prisciandaro Michele , Spallanzani Andrea , Quarà Virginia , Belli Carmen , Vaiani Marta , Curigliano Giuseppe , Cremolini Chiara , De Braud Filippo , Di Bartolomeo Maria , Zagonel Vittorina , Lonardi Sara , Pietrantonio Filippo
Published: April 2021

Background

Immune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs.

Methods

This is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR.

Results

We included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR.

Conclusions

ETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.
Suspecting unwitnessed hypoglycaemia
Authors: Lux Danielle , Edwards Mark , Zhang Liqun
Published: April 2021

Hypoglycaemic coma can present with acute neurological dysfunction mimicking stroke. It may be masked by normoglycaemia due to physiological compensatory mechanisms (Somogyi phenomenon). Specific MR brain scan changes should alert the clinician to consider this alternative to stroke in the acute setting in patients with a history of recurrent hypoglycaemia, even when the blood glucose is not low at presentation. Rapid identification and treatment of hypoglycaemia may confer a good prognosis with radiological resolution.
Prescribed fire shrub consumption in a Sierra Nevada mixed-conifer forest
Authors: Jaffe Melissa R. , Collins Brandon M. , Levine Jacob , Northrop Hudson , Malandra Francesco , Krofcheck Daniel , Hurteau Matthew D. , Stephens Scott L. , North Malcolm
Published: April 2021

Live shrubs in forest understories pose a challenge for mitigating wildfire risk with prescribed fire. Factors driving shrub consumption in prescribed fires are variable and difficult to explain. This study investigated spatial patterns and drivers of Sierra Nevada mixed-conifer forest shrub consumption in prescribed fires through analysis of high-resolution imagery taken before and after prescribed fire. We applied a spatially explicit, generalized additive model to assess tree cover and coarse woody material as potential drivers of shrub consumption. Shrub cover in two experimental stands prior to burning was 38% and 59% and was 36% and 45% one-year post-burn. In both stands shrub patch density increased, while area-weighted mean patch size and largest patch index decreased. Increased local percent cover of coarse woody material was associated with increased shrub consumption. These findings provide information for prescribed fire managers to help better anticipate shrub consumption and patchiness outcomes under similar conditions.
Brunnian braids over the 2-sphere and Artin combed form
Authors: Duzhin Fedor , Loh Sher En Jessica
Published: April 2021

Finding homotopy group of spheres is an old open problem in topology. Berrick et al. derive in [A. J. Berrick, F. Cohen, Y. L. Wong and J. Wu, Configurations, braids, and homotopy groups, J. Amer. Math. Soc. 19 (2006)] an exact sequence that relates Brunnian braids to homotopy groups of spheres. We give an interpretation of this exact sequence based on the combed form for braids over the sphere developed in [R. Gillette and J. V. Buskirk, The word problem and consequences for the braid groups and mapping class groups of the two-sphere, Trans. Amer. Math. Soc. 131 (1968) 277–296] with the aim of helping one to visualize the sequence and to do calculations based on it.
Polynomial invariants, knot homologies, and higher twist numbers of weaving knots W(3,n)
Authors: Mishra Rama , Staffeldt Ross
Published: April 2021

We investigate several conjectures in geometric topology by assembling computer data obtained by studying weaving knots, a doubly infinite family [Formula: see text] of examples of hyperbolic knots. In particular, we compute some important polynomial knot invariants, as well as knot homologies, for the subclass [Formula: see text] of this family. We use these knot invariants to conclude that all knots [Formula: see text] are fibered knots and provide estimates for some geometric invariants of these knots. Finally, we study the asymptotics of the ranks of their Khovanov homology groups. Our investigations provide evidence for our conjecture that asymptotically as [Formula: see text] grows large, the ranks of Khovanov homology groups of [Formula: see text] are normally distributed.
An FFT-based visual quality metric robust to spatial shift
Authors: Chen Guang Yi , Krzyzak Adam
Published: April 2021

Measuring image visual quality is extremely important for many image processing tasks. In the past, several metrics have been proposed for measuring image visual quality such as structural similarity index (SSIM) and visual information fidelity (VIF). Nevertheless, these metrics are not robust to image spatial shifts when the reference and distorted images are misaligned by a few pixels. These metrics generate extremely low metric scores which is undesirable. It is well known that shifting the image by a few pixels does not affect the perceived image quality significantly. In this paper, we modify the SSIM metric to make it more robust to spatial shifts by pre-processing the input images with two-dimensional (2D) Fast Fourier Transform (FFT2). We then use the magnitudes of the Fourier coefficients in the existing metrics since these coefficients are shift-invariant. Experiments show that our proposed novel method is particularly good at measuring the visual quality of 2D images because it is far less complex than the existing methods and it offers better accuracy. Our new method is better than SSIM even when no spatial shifts are introduced to the images.
Synthesis and spectroscopic properties of BODIPY-dithienylethene conjugates
Authors: Yao Shengxin , Shen Zhen
Published: April 2021

Two red fluorescent triads containing photochromic dithienylethene moiety linked to two 4,4-difluoro-4-bora-3[Formula: see text],4[Formula: see text]-diaza-[Formula: see text]-indacene (BODIPY) via acetylene bond, 1a or single bond, 1b were synthesized and characterized. Although no evident absorption and NMR spectra changes were observed upon irradiation with visible light, the absorption and fluorescence spectra of 1a and 1b are remarkably solvent dependent, in contrast to those of the reference BODIPY-thienyl compounds 2a and 2b, which are essentially solvent independent. Fluorescence intensities of 1a and 1b decreased as the solvent polarity increased, and the fluorescence decay showed two exponentials in polar solvents other than [Formula: see text]-hexane. DFT calculations have been carried out to elucidate the spectral behavior of investigated compounds.
A Composite Material of Hydrothermal Prepared Blue Fescue-Like CQDs/Sn-Doped ZnO with Enhanced Visible Light-Driven Photocatalytic Activity
Authors: Rong Runce , Wang Limin , Zang Hongjun
Published: April 2021

Novel Blue Fescue-like CQDs/Sn-doped ZnO composite photocatalyst was successfully synthesized via a gentle hydrothermal method. The hierarchical CQD/Sn-doped ZnO samples are assembled by many hexagonal prism-shaped nanoneedles. In addition, the photocatalytic performance of all samples was obtained by degrading rhodamine B(RhB) under visible light irradiation. The degradation results indicate that the photocatalytic activity of CQDs/Sn-doped ZnO is better than Sn-doped ZnO, CQDs/ZnO, pure CQDs and pure ZnO. The stability and reusability of CQDs/Sn-doped ZnO were confirmed by cyclic degradation experiments. It can be considered that the effective photocatalytic performance is attributed to the adsorption and transfer of electrons by CQDs.
Thickness of skeletons of arithmetic hyperbolic orbifolds
Authors: Alpert Hannah , Belolipetsky Mikhail
Published: April 2021

We show that closed arithmetic hyperbolic 3-dimensional orbifolds with larger and larger volumes give rise to triangulations of the underlying spaces whose 1-skeletons are harder and harder to embed nicely in Euclidean space. To show this we generalize an inequality of Gromov and Guth to hyperbolic n-orbifolds and find nearly optimal geodesic triangulations of arithmetic hyperbolic 3-orbifolds.
A Natural Product Chemist's Guide to Unlocking Silent Biosynthetic Gene Clusters
Authors: Covington Brett C. , Xu Fei , Seyedsayamdost Mohammad R.
Published: April 2021

Microbial natural products have provided an important source of therapeutic leads and motivated research and innovation in diverse scientific disciplines. In recent years, it has become evident that bacteria harbor a large, hidden reservoir of potential natural products in the form of silent or cryptic biosynthetic gene clusters (BGCs). These can be readily identified in microbial genome sequences but do not give rise to detectable levels of a natural product. Herein, we provide a useful organizational framework for the various methods that have been implemented for interrogating silent BGCs. We divide all available approaches into four categories. The first three are endogenous strategies that utilize the native host in conjunction with classical genetics, chemical genetics, or different culture modalities. The last category comprises expression of the entire BGC in a heterologous host. For each category, we describe the rationale, recent applications, and associated advantages and limitations.
Liquid–Liquid Chromatography: Current Design Approaches and Future Pathways
Authors: Morley Raena , Minceva Mirjana
Published: April 2021

Since its first appearance in the 1960s, solid support–free liquid–liquid chromatography has played an ever-growing role in the field of natural products research. The use of the two phases of a liquid biphasic system, the mobile and stationary phases, renders the technique highly versatile and adaptable to a wide spectrum of target molecules, from hydrophobic to highly polar small molecules to proteins. Generally considered a niche technique used only for small-scale preparative separations, liquid–liquid chromatography currently lags far behind conventional liquid–solid chromatography and liquid–liquid extraction in process modeling and industrial acceptance. This review aims to expose a broader audience to this high-potential separation technique by presenting the wide variety of available operating modes and solvent systems as well as structured, model-based design approaches. Topics currently offering opportunities for further investigation are also addressed.
Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19
Authors: Miličić Stanić Branka , Maddox Sydney , de Souza Aline M. A. , Wu Xie , Mehranfard Danial , Ji Hong , Speth Robert C. , Sandberg Kathryn
Published: April 2021

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in Ace2 knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.
Alternatively Expressed Transcripts Analysis of Non-Small Cell Lung Cancer Cells under Different Hypoxic Microenvironment
Authors: Wang Shunjun , Ma HuSai , Li Huayang , Liu Quan , Huang Suiqing , Huang Lin , Luo Li , Jiang Yupeng , Wu Zhongkai
Published: April 2021

Globally, non-small cell lung cancer (NSCLC) is the most fatal form of malignancy. Numerous studies have shown that people living at high altitudes are at a higher risk for cancer. Hypoxia is one of the most important features in high altitude area. Compared with normal cells, cancer cells are more adapted to hypoxia atmosphere. However, at high altitudes, hypoxic conditions are also accompanied by other altered environmental conditions. To identify the single influence of hypoxia, we performed second-generation sequencing to identify gene expression changes triggered by the different oxygen concentrations. We identified 782 genes in A549 cells and 1122 genes in H520 cells that showed altered expression by the combined analysis in 5% oxygen concentration group and 1% oxygen concentration group control group. We further analyzed these targets and found 113 genes altered in both cell lines. Interestingly, we found KxD1 was the only one in both top 10 lists. Further analysis revealed KxD1 to be significantly elevated in NSCLC patients and negatively correlated with prognosis in stage I and II NSCLC patients. Moreover, this correlation reversed in stage III patients. Additionally, compared with patients who only received clean margin operation or chemotherapy, patients who received radiotherapy also showed opposite result. Thus, KxD1 may be a promising target for the treatment of NSCLC in high-altitude areas.
Mutational Analysis of a Familial Adenomatous Polyposis Pedigree with Bile Duct Polyp Phenotype
Authors: Xie Li-jun , Ruan Dan-dan , Zhang Jian-hui , Li Yi , Chen Li , Yan Mao-lin , Yu Ming-dian , Luo Jie-wei , Zhang Hui-zhen
Published: April 2021

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs

∗

31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.
Radial Undersampling‐Based Interpolation Scheme for Multislice CSMRI Reconstruction Techniques
Authors: Murad Maria , Jalil Abdul , Bilal Muhammad , Ikram Shahid , Ali Ahmad , Khan Baber , Mehmood Khizer
Published: April 2021

Magnetic Resonance Imaging (MRI) is an important yet slow medical imaging modality. Compressed sensing (CS) theory has enabled to accelerate the MRI acquisition process using some nonlinear reconstruction techniques from even 10% of the Nyquist samples. In recent years, interpolated compressed sensing (iCS) has further reduced the scan time, as compared to CS, by exploiting the strong interslice correlation of multislice MRI. In this paper, an improved efficient interpolated compressed sensing (EiCS) technique is proposed using radial undersampling schemes. The proposed efficient interpolation technique uses three consecutive slices to estimate the missing samples of the central target slice from its two neighboring slices. Seven different evaluation metrics are used to analyze the performance of the proposed technique such as structural similarity index measurement (SSIM), feature similarity index measurement (FSIM), mean square error (MSE), peak signal to noise ratio (PSNR), correlation (CORR), sharpness index (SI), and perceptual image quality evaluator (PIQE) and compared with the latest interpolation techniques. The simulation results show that the proposed EiCS technique has improved image quality and performance using both golden angle and uniform angle radial sampling patterns, with an even lower sampling ratio and maximum information content and using a more practical sampling scheme.
Ant Colony Optimization Inversion Using the L1 Norm in Advanced Tunnel Detection
Authors: Ma Zhao , Nie Lichao , Zhou Pengfei , Deng Zhaoyang , Guo Lei
Published: April 2021

During the construction of the tunnel, there may be water-bearing anomalous structures such as fault fracture zone. In order to ensure the safety of the tunnel, it is necessary to carry out advanced tunnel detection. The traditional linear inversion method is highly dependent on the initial model in the tunnel resistivity inversion, which makes the inversion results falling into the local optimal optimum rather than the global one. Therefore, an inversion method for tunnel resistivity advanced detection based on ant colony algorithm is proposed in this paper. In order to improve the accuracy of tunnel advanced detection of deep anomalous bodies, an ant colony optimization (ACO) inversion is used by integrating depth weighting into the inversion function. At the same time, in view of the high efficiency and low cost of one-dimension inversion and the advantages of L1 norm in boundary characterization, a one-dimensional ant colony algorithm is adopted in this paper. In order to evaluate the performance of the algorithm, two sets of numerical simulations were carried out. Finally, the application of the actual tunnel water-bearing anomalous structure was carried out in a real example to evaluate the application effect, and it was verified by excavation exposure.
Characterization of the Key Aroma Compounds in the Fruit of Litsea pungens Hemsl. (LPH) by GC-MS/O, OAV, and Sensory Techniques
Authors: Pu Dandan , Shan Yimeng , Duan Wen , Huang Yan , Liang Li , Yan Yi , Zhang Yuyu , Sun Baoguo , Hu Guanghui
Published: April 2021

The key aroma compounds in the fruit of Litsea pungens Hemsl. (LPH) were concentrated through solvent-assisted flavor evaporation (SAFE) and characterized by gas chromatography-mass spectrometry-olfactometry (GC-MS/O), quantitative descriptive analysis (QDA), odor activity values (OAVs), and addition test. The results showed that LPH contained 31 aroma-active compounds (flavor dilution, FD = 9). Among them, 30 odorants were quantified by the standard curve method. The OAV analysis results showed that 25 odorants had OAVs ≥ 1, which could be considered as the potent odorants. D-Limonene and 3,7-dimethyl-2,6-octadienal had the highest OAVs (OAV = 9803 and 8399), followed by (Z)-3,7-dimethylocta-2,6-dienal (OAV = 1893), β-myrcene (OAV = 1798), (E)-3-phenyl-2-propenoic acid ethyl (OAV = 1603), and β-caryophyllene (OAV = 1129). Addition experiments further confirmed that 3,7-dimethyl-2,6-octadienal, (Z)-3,7-dimethylocta-2,6-dienal, and D-limonene contributed to lemon attribute, β-myrcene contributed to green attribute, citronellal contributed to mint and fresh note, and eucalyptol contributed to eucalyptus-like note were the key odorants.
Design of the Internet plus Drug Circulation Business Model Based on Value Chain
Authors: Liang Linmeng
Published: April 2021

With the continuous development of computers and the Internet, all industries in China have brought new opportunities for change, and pharmaceutical e-commerce has also shown great potential for development. With the call and encouragement of national policies, the “Internet + drug distribution” business model has shown great potential to replace the traditional drug distribution model in the near future due to its advantages of shortening the transaction process and reducing the cost of enterprises. This paper presents a literature review on theories related to “Internet + drug distribution,” value chain and business model at home and abroad, and focuses on how traditional drug distribution enterprises should adopt the “Internet + drug distribution” model when the country is vigorously promoting it. The study focuses on how traditional pharmaceutical distribution companies should innovate their business models from the perspective of value chain to seek better development. By comparing the business models before and after the innovation, the new business model of “Internet + drug distribution” can help enterprises establish diversified value propositions, increase revenue channels, and reduce operating costs. At the same time, it can integrate and innovate the internal and external value chains of enterprises, so that traditional pharmaceutical distribution enterprises can further enhance their competitiveness and expand their market share. This thesis can enrich the application of value chain and business model theories in the field of “Internet + drug distribution,” and it is hoped that the model experience developed in this thesis can be used as a reference for similar enterprises in their transformation process.
Inactivation of Different Salmonella enteriditis Phage Types and Safety and Efficacy of Inactivated Products in Chicken
Authors: Akhtar A. , Hair-Bejo M. , Hussein Elawad A. , Zakaria Zunita
Published: April 2021

This study was conducted to inactivate Salmonella enteriditis phage types (SE pt) and to determine the safety and efficacy of inactivated SE pt in chickens. SE pt 1, 3A, 6A, 7, and 35 were inactivated and inoculated (0.20 mL) in 124 chickens divided into 6 groups (CV1, CV3A, CV6A, CV7, CV35, and CV0 as a control). Sampling was conducted on day 14 after inoculation (pi). Eight chickens from each group were separated on day 14 pi for oral challenge with 0.20 mL/chicken (1010 cfu/mL) SE pt 6A and designated CV1C, CV3AC, CV6AC, CV7C, CV35C, and CV0C as control chickens. On days 7 and 14 postchallenge (pc), 4 chickens from every group were sacrificed for sampling. There was no significant difference in the body weight between different groups. In challenged groups, there was no significant association between different tissues and isolation of Salmonella on days 7 and 14 pc. There was significance (p < 0.05) in isolation of Salmonella when CV0C group was compared with other challenged groups. Significance was not observed between different tissues with respect to induction of microscopic changes. Significance was not observed between day 7 pc and day 14 pc with respect to scoring of lesions induced. Clinical signs and gross lesions were also recorded. ELISA was applied. Only in CV3AC group, the mean antibody titer was 1359 on day 14 pc. The conclusion was that inactivated SE pt 3A and 6A were safe and efficacious for protection against Salmonella enteriditis infection in chickens.
A Continuous Nonlinear Fractional-Order PI Controller for Primary Frequency Control Application
Authors: Elyaalaoui Kamal , Labbadi Moussa , Ouassaid Mohammed , Cherkaoui Mohamed
Published: April 2021

In this paper, a nonlinear fractional-order PI (NL-FO-PI) controller is proposed for primary frequency control (PFC) of a wind farm based on the squirrel cage induction generator. The new structure composites a fractional-order operator and nonlinear function to achieve better control performance for the PFC system. The benchmarking process is demonstrated by investigating the performance of fractional-order PI (FO-PI) and nonlinear PI (NL-PI) controllers. Initially, the controller is applied to a single-area power system for design and stability study and then extended to the two-area interconnected wind farm to validate the applicability in the more realistic power system. The proposed control method ensures the balance of power and keeps the system frequency within a suitable range. The simulation results demonstrate that the proposed NL-FO-PI controller provides less percentage overshoot, settling time, rise time, and peak time than other controllers.
Food Insecurity Is an Independent Risk Factor for Depressive Symptoms in Survivors of Digestive Cancers
Authors: Madigan Katelyn E. , Leiman David A. , Palakshappa Deepak
Published: April 2021

Background:

Colorectal and other digestive cancer survivors are at increased risk of depression, which can negatively affect health outcomes. Food insecurity (FI), the lack of consistent access to enough food, can also contribute to these health complications. The objective of this study was to determine the relationship between FI and depressive symptoms within this population.

Methods:

We conducted a cross-sectional analysis of data from the 2007–2016 National Health and Nutrition Examination Survey. We included all adults (≥20 years) with a self-reported history of a digestive cancer (including colorectal, esophageal, stomach, liver, and pancreas cancer). Our primary exposure was household FI, and our outcome of interest was depressive symptoms, as measured by the validated 9-item Patient Health Questionnaire. We used multivariable ordinal logistic regression to test the association between FI and depressive symptoms, controlling for demographic and clinical covariates.

Results:

We included 229 adult digestive cancer survivors (weighted N = 1,510,579). The majority of the study sample was female and non-Hispanic White with mean of 11.0 years since cancer diagnosis; 14.3% reported FI. In multivariable models controlling for demographic and clinical covariates, we found that food insecure digestive cancer survivors had significantly higher odds of depressive symptoms than food secure digestive cancer survivors (OR: 3.25; 95% confidence interval: 1.24–8.55; P = 0.02).

Conclusions:

Among a nationally representative sample of colorectal cancer and other digestive cancer survivors, FI was associated with increased odds of depressive symptoms.

Impact:

This study adds further evidence to the negative impact FI may have on survivors' physical and mental health.
Abstract IA-004: The impact of gut microbiota on the radiotherapy-induced antitumor immune response
Authors: Uribe-Herranz Mireia , Rafail Stavros , Beghi Silvia , Verginadis Ioannis , Mesaros Clementina , Koumenis Costantinos , Facciabene Andrea
Published: April 2021

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

Citation Format: Mireia Uribe-Herranz, Stavros Rafail, Silvia Beghi, Ioannis Verginadis, Clementina Mesaros, Costantinos Koumenis, Andrea Facciabene. The impact of gut microbiota on the radiotherapy-induced antitumor immune response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-004.
Abstract IA-015: Hypoxia-induced SETX links replication stress with the unfolded protein response
Authors: Hammond Ester M.
Published: April 2021

Tumor hypoxia is associated with poor patient prognosis and radiation resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, DNA replication rates decrease and radiosensitivity increases. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

Citation Format: Ester M. Hammond. Hypoxia-induced SETX links replication stress with the unfolded protein response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-015.
Abstract IA-020: Optimizing stem cell niche for post-irradiation regeneration
Authors: Coppes Rob P.
Published: April 2021

Radiotherapy involves unavoidable co-irradiation of the normal tissue, often resulting in side effects that limit the dose to the tumor and/or reduce quality of life of cancer survivors. The response of normal tissues to irradiation is mainly determined by the survival and regenerative potential of the tissue stem cells, and modulated by inflammatory processes, vasculature damage, altered neuronal innervation and fibrosis. Indeed, transplantation of tissue specific stem cells has been shown to restores tissue homeostasis and prevent late radiation effects. However, the radiation-induced senescence, fibrosis, and chronic inflammation may chance the stem cell niche engender an unfavorable environment for the regenerative potential of the tissue’s stem cells. Here changes in the salivary gland stem cell niche will be discussed using irradiated murine submandibular salivary gland tissue and derived organoids. Recently, we have developed methods to culture murine and patient specific tissue resembling salivary gland organoids (SGO). SGO contain all the glandular lineages, are able to extensively self-renew and up on transplantation rescue salivary gland function, allowing the study of radiation responses. The role of stemness factors, senescence and inflammatory processes in stem cell self-renewal and differentiation and post-irradiation regeneration will be discussed. Using SGO formation efficiency (OFE) as a measure of regenerative potential it is shown that stem cell potency after in vivo irradiation, is time dependent reduced. Interestingly, the conditioned medium of irradiated SGO reduced the OFE of unirradiated SGO. The potential role of radiation-induced senescence-associated secretory phenotype, hippo-signaling and inflammation through activation of cytosolic DNA sensing pathways on stem cells function will be addressed. Radiation-induced environmental changes in the stem cells niche have a severe impact on stem cell function. Modulation of these effect may enhance regenerative potential of surviving stem cells and improve engraftment and regeneration after stem cell transplantation. Supported by the Dutch Cancer Society (KWF, grant No. 10650 and 12092) and The Netherlands Organisation for Health Research and Development (ZonMw, Grant nrs. 11.600.1023 and 40-43600-98-14003).

Citation Format: Rob P. Coppes. Optimizing stem cell niche for post-irradiation regeneration [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-020.