bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract NG02: Identification of high priority genes for basic and translational pancreatic cancer research
Authors: Nwosu Zeribe Chike , Giza Heather C. , Charlestin Verodia , Nassif Maya , Kim Daeho , Kemp Samantha , Steele Nina G. , Lyssiotis Costas A. , Pasca di Magliano Marina
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and drug resistant and is one of the most lethal solid malignancies. Genomic profiling studies have defined the molecular subtypes and mutational landscape of PDAC and extensive gene expression profiling dataset have been accumulated to date. However, there is a knowledge gap on the consistency of gene expression across profiled PDAC samples and this limits the prospects of clinical translation. To facilitate novel drug target prioritization and biomarker discovery, we have extensively analyzed over 20 publicly accessible datasets. We report the most consistently expressed genes in PDAC tissues compared to non-tumors. Specifically, we identified 3,938 consistent genes, including 2,010 consistently upregulated genes, topmost of which included LAMC2, TMPRSS4, S100P, SLC6A14, COL10A1, CTSE, LAMB3, CEACAM5/6, and glucose transporter SLC2A1, and 1,928 consistently downregulated genes top among which include AOX1, IAPP, albumin (ALB), SERPINI2, PDK4 and PNLIPRP1/2 (adjusted P<0.05). Over 50% of the genes are unknown. In addition, these genes largely reflected the same expression pattern in bulk and single cell RNA sequencing analysis, showed tumors-specificity, and correlated with several cancer indices including proliferation, metastasis, mutation and tumor grade. Pathway enrichment analyses revealed ‘pathways in cancer', ‘focal adhesion', ‘p53', ‘cell cycle', ‘transcription factor binding', “glycolysis” among upregulated processes. These pathway alterations were accompanied by profound metabolic alterations and signatures of disrupted pancreatic homeostasis. Interactome and disease ontology analyses further linked the consistent genes with precancerous conditions, PDAC, and malignancy. We found that ~41% of the genes predicted patients' overall survival in at least two datasets while clustering analyses and receiver operating characteristic analysis uncovered highly probable biomarkers. Subsequent analysis of gene silencing datasets identified 185 ‘high-priority' genes (notably candidates in cell cycle and glycolysis) whose knockdown suppress PDAC viability. Our multi-dimensional analysis is an important milestone in the quest for mechanisms, drug targets and biomarkers in PDAC, and outlines an adaptable analytical approach that can aid biomarker or therapeutic target discovery in other cancers.

Citation Format: Zeribe Chike Nwosu, Heather C. Giza, Verodia Charlestin, Maya Nassif, Daeho Kim, Samantha Kemp, Nina G. Steele, Costas A. Lyssiotis, Marina Pasca di Magliano. Identification of high priority genes for basic and translational pancreatic cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG02.
Abstract PL01-04: Epigenetic mechanisms of malignant clonal dominance and immune evasion
Authors: Dawson Mark A.
Published: July 2021

All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary trajectories and clonal fitness imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. In this presentation I will discuss some of our recent work addressing the significance of transcriptional processes that facilitate malignant clonal dominance in isogenic cancer cells. I will also highlight emerging evidence showing the importance of manipulating transcriptional regulators to facilitate anti-cancer immune surveillance in a broad range of cancers.

Citation Format: Mark A. Dawson. Epigenetic mechanisms of malignant clonal dominance and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL01-04.
Abstract PL03-02: (Re)emerging principles of cancer therapy
Authors: Kaelin William George
Published: July 2021

It is likely that some of the mutations that occur late during evolution, whether passenger mutations or passenger mutations, are likely only tolerated (let alone advantageous to the cancer cell) because of the mutations that preceded them. If so, targeting mutations that occur early during tumor evolution should selectively kill cancer cells by unmasking the otherwise deleterious effects of subsequent mutations. There are now many precision cancer drugs that target such early mutations, including EGFR inhibitors for lung cancer, c-Kit mutations for GI stromal tumors, and B-Raf inhibitors for B-Raf mutant melanomas. Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is an early event in kidney cancer. Inactivated proteins can sometimes be tackled by exploiting epistatic relationships or synthetic lethality. For example, pVHL suppresses the HIF2 transcription factor, which in turn regulates VEGF. VEGF inhibitors are now mainstays of kidney cancer treatment. HIF2 was viewed as “undruggable”, but undruggable proteins can sometimes be targeted by allosteric modulators or degraders. A first-in-class allosteric HIF2 inhibitor has advanced to phase 3 trials based on promising early data. Most cancer drugs work better in the frontline setting, and a recent study of previously untreated von Hippel-Lindau disease patients strongly suggests this will be true for the HIF2 inhibitor. Combination therapy will be required to cure most cancer. It is tempting to combine drugs that have interdependent actions in an attempt to achieve synergy, but this increases the risk of cross-resistance. The classical way to prevent resistance is to combine drugs that have distinct mechanisms of action (to minimize toxicity and cross-resistance). In this regard, immunotherapy has emerged as a powerful modality to treat cancer cells, and complements therapies aimed at inducing cancer cell death. Both kidney cancer and melanomas are highly immunogenic and can respond to immune checkpoint blockade, yet kidney cancer has a much lower mutational burden than melanoma. Recent work suggests that kidney cancers promiscuously express endogenous retroviruses, which might serve as a source of neoantigens. If true, it might be possible to pharmacologically enhance ERV expression to augment immunotherapy.

Citation Format: William George Kaelin. (Re)emerging principles of cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-02.
Abstract SY01-03: The gold standard cancer diagnosis: Studies of physician variability, interpretive behavior, and the impact of AI
Authors: Elmore Joann
Published: July 2021

The current gold standard for cancer diagnoses is based on pathologists' visual inspection of tissue sections. However, our research has found concerning levels of inter-observer and intra-observer variability among pathologists. Our prior work in melanoma shows that current diagnoses within the disease spectrum from benign nevi to melanoma in situ to invasive melanoma are neither reproducible nor accurate, yielding estimates that ~17% of all diagnoses for melanocytic lesions in the US are incorrect (Elmore et al. BMJ 2017). A study conducted by our team in breast pathology quantified the magnitude of diagnostic agreement among pathologists compared with a gold standard consensus reference: among DCIS cases, 16% of interpretations were discordant, while among atypia cases 52% of interpretations were discordant (Elmore et al. JAMA 2015). While computer systems, such as computer aided detection (CAD) tools, have been widely integrated into clinical practice to aid the interpretative and diagnostic process, our work has also found that the use of CAD can be associated with increases in potential harms, including higher recall and biopsy rates for screening mammography (Fenton et al. NEJM 2007). Given the critical need to improve the quality of our current diagnostic and prognostic capabilities, our multidisciplinary research team is conducting several studies that involve the development and integration of AI/machine learning and eye-tracking across clinical contexts. The challenges and implications associated with “gold standard” definitions for diagnoses, with data sharing infrastructure and with the eventual impact of AI on the human interface will be discussed.

Citation Format: Joann Elmore. The gold standard cancer diagnosis: Studies of physician variability, interpretive behavior, and the impact of AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY01-03.
Abstract SY19-01: TGFβ and immune evasion in metastatic cancer
Authors: Massagué Joan
Published: July 2021

TGF-β and Immune Evasion in Metastatic Cancer Transforming growthfactor-β (TGF-β) is a major regulator of development,immune homeostasis, tissue regeneration, and cancer. TGF-β signaling suppresses tumor initiation but promotestumor progression through mechanisms that are increasingly understood. TGF-β inhibitsthe expansion and function of many components of the immune system and itspresence in the tumor microenvironment limits the effectiveness of current immunotherapies. To betterdefine the potential benefit of targeting TGF-β in cancer, we investigated therole of TGF-β in metastasis. Metastasis, the main cause of deathfrom cancer, is driven by stem-like disseminated cancer cells (“metastasisinitiating cells”, MICs) capable of reversible quiescence, immune evasion, organ-specificoutgrowth, and drug resistance. We developed models oflung adenocarcinoma (LUAD) metastatic dormancy and outbreak by isolating MICs thatrecapitulate the developmental and regenerative phenotypes of carcinoma cellsin human metastases. We find that TGF-β in thetumor microenvironment has different tumorigenic effects on early-stageprogenitor MICs and their progenies. In SOX2-rich early progenitor MICs, TGF-βinduces dormancy by imposing a growth-inhibited epithelial to mesenchymaltransition (EMT). Pharmacologic inhibition of TGF-β in this context causes MICsto exit from this immune evasive dormancy and become exposed to immune attack. Incontrast, SOX9-rich MIC progeny cells respond to TGF-β with an EMT that iscoupled to expression of fibrogenic cytokines. Deletion of TGF-β receptor orits fibrogenic target genes in the carcinoma cells prevents intratumoralfibrosis and inhibits metastatic outgrowth. These insights suggest that targetingTGF-β in metastatic cancer can improve treatment outcomes by forcing MICs outof immune evasive quiescence and suppressing intra-tumoral fibrosis, inaddition to relieving innate and adaptive immunity from TGF-β mediated inhibition.

Citation Format: Joan Massagué. TGFβ and immune evasion in metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY19-01.
Abstract SY26-01: Targeting natural ligands for TCR engineering
Authors: Schoenberger Stephen P.
Published: July 2021

Neoantigens (NeoAg) offer the potential to directtherapeutic T cell responses to immunogenic mutations exclusively expressed bytumors. Most strategies for their identification select potentialligands for CD8+ T cells rather than for CD4+ T cells,despite the extensive literature showing functional cooperation between thesesubsets. To better understand CD4-CD8synergy in anti-tumor immunity, we have applied a novel functional approach toidentify the subset of expressed mutations targeted as NeoAg by natural CD4+and CD8+ T cell responses to a poorly-immunogenic spontaneoussquamous cell tumor, SCC VII. We demonstrate that a single mutation (Cltc H129>Q) that is recognized byboth subsets is capable of eradicating large established SCCVII tumors in thesetting of therapeutic vaccination provided the relevant epitopes whenphysically linked. Single-cell TCR analysis revealed that the endogenous CD4+T cell response against this epitope comprises both low-affinity CD4+-dependentand high-affinity CD4+-independent receptors, with the latterdisplaying superior capacity in promoting prophylactic and therapeutic CD8+T cell-mediated immunity against the MHC class I+ class II−tumors in the setting of adoptive cellular therapy. These findings demonstratethat linked CD4+ T cell help enables potent therapeuticNeoAg-specific vaccination and provides instructive insights into the qualityof TCRs mediating this effect.

Citation Format: Stephen P. Schoenberger. Targeting natural ligands for TCR engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY26-01.
Abstract 17: Adaptation and Assessment of a Text Message Cessation Intervention for Tobacco Users in Viet Nam
Authors: Shelley Donna , Jiang Nan , Cleland Charles , Nguyen Trang , Abroms Lorien , Nguyen Nam
Published: July 2021

Purpose: Text message (i.e., short message service, SMS) smoking cessation interventions have demonstrated efficacy, but most evaluations were conducted in high-income countries. We assessed the feasibility, acceptability and preliminary efficacy of a smoking cessation SMS intervention adapted to the sociocultural context, language and communication styles of Vietnamese smokers.

Methods: Participants were current adult cigarette-only or dual cigarette and waterpipe users. We adapted a message library from two SMS smoking cessation programs with proven efficacy in increasing quit rates in the US. The iterative adaptation process included focus groups with 58 smokers to provide data on culturally relevant patterns of tobacco use and to assess message preferences. We then pilot tested (n=40) a 6-week SMS intervention using brief text surveys to obtain real time feedback on messages and conducted post-test interviews (n=10) to inform further adaptation. Finally, we randomized 100 smokers to the SMS intervention (including bidirectional messages and key words to generate additional support) vs. weekly text assessments of tobacco use. Surveys assessed engagement and acceptability at 6 weeks, cessation at 6 and 12 weeks.

Results: Significant modifications were made in terms of content (e.g. preference for negative framing of health risks, and focus on enhancing refusal skills) and tone (e.g., preferences for action-oriented advice for craving management). We found high rates of engagement (e.g. 82% usually or always read messages) and satisfaction with the SMS program (e.g. 70% satisfied, 24% very satisfied).

Conclusion: Intervention participants suggested enhancing the program with additional telephone support, extending the length of the program, and adding images and more interactive content. This pilot study provided support for the feasibility and acceptability of culturally-adapted SMS smoking cessation treatment among smokers in Viet Nam. It also showed promising early efficacy in promoting abstinence. Future studies are needed to assess whether, with additional modifications, the program is associated with long-term abstinence.

Citation Format: Donna Shelley, Nan Jiang, Charles Cleland, Trang Nguyen, Lorien Abroms, Nam Nguyen. Adaptation and Assessment of a Text Message Cessation Intervention for Tobacco Users in Viet Nam [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 17.
Immune-Related Meningoencephalitis following Nivolumab in Metastatic Renal Cell Carcinoma
Authors: Shields Lisa B.E. , Alsorogi Mohammad S. , Mar Nataliya , Rezazadeh Kalebasty Arash
Published: July 2021

While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.
Multimodal Imaging in a Case with Bilateral Choroidal Folds
Authors: Xu David , Faridi Ambar
Published: July 2021

We highlight the use of multimodal imaging to diagnose and report what is, to our knowledge, a novel presentation of bilateral choroidal neovascularization (CNV) and prominent macular choroidal folds (CFs) in a patient with pattern dystrophy. An 81-year-old Caucasian male presented with painless, blurry central vision in both eyes. Color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), fundus autofluorescence, and brightness scan ultrasonography supported the diagnosis of pattern dystrophy with bilateral CNV and CF. In the right eye, visually significant CNV worsened post-bevacizumab treatment but responded well to aflibercept. During 4-year follow-up, Snellen visual acuity remained excellent in both eyes at 20/20, including the treatment-naïve left eye. CFs remained markedly stable in both eyes.
Percentage of Age-Predicted Cardiorespiratory Fitness Is Inversely Associated with Cardiovascular Disease Mortality: A Prospective Cohort Study
Authors: Laukkanen Jari A. , Kurl Sudhir , Khan Hassan , Zaccardi Francesco , Kunutsor Setor K.
Published: July 2021

Introduction: Percentage of age-predicted cardiorespiratory fitness (% age-predicted CRF) is a potentially useful cardiopulmonary exercise testing (CPX) parameter, but there are limited data on its prognostic relevance for adverse cardiovascular disease (CVD) outcomes. We aimed to assess the association of % age-predicted CRF with CVD mortality and the extent to which % age-predicted CRF measurements could improve the prediction of CVD mortality. Methods: Peak oxygen uptake, used as the measure of CRF, was directly assessed in 2,276 men who underwent CPX. The age-predicted CRF estimated from a regression equation for age was transformed to % age-predicted CRF with the following formula: (achieved CRF/age-predicted CRF) × 100. Hazard ratios (HRs) (95% confidence intervals [CIs]) and measures of risk discrimination for CVD mortality were calculated. Results: During a median follow-up of 28.5 years, 643 fatal CVDs were recorded. The relationship between % age-predicted CRF and CVD mortality was dose response in nature. In analysis adjusted for conventional risk factors, one standard deviation increase in % age-predicted CRF was associated with a reduced risk of CVD mortality (HR 0.61; 95% CI: 0.56–0.67), which was minimally attenuated on further adjustment for several other confounders (HR 0.71; 95% CI: 0.64–0.78). Addition of % age-predicted CRF to a CVD mortality risk prediction model containing established risk factors significantly improved risk discrimination and reclassification. Conclusion: Percentage of age-predicted CRF is inversely and independently associated with CVD mortality in a graded fashion and significantly improves the prediction and classification of the long-term risk for CVD mortality beyond established risk factors.
Alteration of Histopathology in Recurrent Nasal Polyps
Authors: Wang Feng , Yang Yang , Chen Haihong
Published: July 2021

Objective: The objective of this study was to analyze the histopathologic changes in recurrent nasal polyps (NPs) in terms of tissue inflammatory cells infiltration and mucosal remodeling. Methods: Thirty-five patients with primary NPs requiring a revision surgery during follow-up and a matched control group of 35 primary NP patients without recurrence were retrospectively enrolled. Histopathologic examination was performed of tissue inflammatory cells, subepithelial edema, epithelial cell hyperplasia, basement membrane thickness, and fibrosis. Results: The mean eosinophil and neutrophil counts, proportions of eosinophil and neutrophil, as well as total inflammatory cell count were significantly higher in the recurrent group than those in the controls. Higher subepithelial edema was seen in the recurrent group. Within the recurrent group, the mean tissue eosinophil count and relative eosinophilia reduced from the first operation to revision surgery, whereas neutrophil count and proportion, and total inflammatory cell counts remained unchanged. Subepithelial edema and epithelial cell hyperplasia were significantly reduced after the first surgical procedure. Conclusion: NP recurrence is associated with higher inflammatory grade (especially in eosinophilia and neutrophilia). Surgical and corticoid treatments may have an impact on mucosal histopathologic changes but need further certification.
Epidemiology of Distal Renal Tubular Acidosis: A Study Using Linked UK Primary Care and Hospital Data
Authors: Bianic Florence , Guelfucci Florent , Robin Ludovic , Martre Catherine , Game David , Bockenhauer Detlef
Published: July 2021

Introduction: Distal renal tubular acidosis (dRTA), or RTA type 1, a rare inherited or acquired disease, is a disorder of the distal tubule caused by impaired urinary acid secretion. Due to associated conditions and nonspecific symptoms, dRTA may go undetected. This analysis aims to estimate the prevalence of dRTA in the UK Clinical Practice Research Datalink (CPRD) databases and extrapolate it to European Union Five (EU5) populations. Methods: A retrospective analysis was conducted using the CPRD GOLD database and linked Hospital Episode Statistics (HES) data to identify diagnosed and potentially undiagnosed or miscoded patients (suspected patients). Patients’ records with at least one diagnosis code for dRTA, RTA, specific autoimmune diseases, or renal disorders recorded between January 1987 and November 2017 were obtained and analyzed. An algorithm was developed to detect potentially undiagnosed/miscoded dRTA, based on associated conditions and prescriptions. Results: A total of 216 patients with diagnosis of RTA or dRTA were identified (with 98 linked to hospital data), and 447 patients were identified as having suspected dRTA. dRTA prevalence for 2017 was estimated between 0.46 (recorded cases, of which 22.1% were considered primary) and 1.60 when including suspected cases (7.6% primary) per 10,000 people. Prescription and clinical records of diagnosed patients revealed a wide range of comorbidities and a need for pharmacological treatment to manage associated symptoms. Conclusion: The study provides new estimates of dRTA prevalence in Europe and suggests that patients may often be unreported or miscoded, potentially confounding appropriate disease management.
ANCA Vasculitis Recurrence in Hemodialysis Patients: The Role of Rituximab
Authors: Oliveira João , Bernardo João , Fonseca José , Marques Filipe , Gameiro Joana , Outerelo Cristina , Jorge Sofia
Published: July 2021

Antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) is characterized by systemic inflammation and is the most common cause of new-onset glomerulonephritis in adults older than 50 years. Renal disease secondary to AAV can lead to chronic kidney disease (CKD) requiring renal replacement therapy in approximately 20–25% of patients. Relapses are infrequent in the population on dialysis, and treatment guidelines do not specify these patients. Reports regarding the clinical course, survival, or relapse rate after beginning dialysis are scarce. The authors present 3 cases of CKD patients on hemodialysis who presented with AAV relapse, successfully treated with rituximab, and provide a literature review on relapse treatment.
Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy
Authors: Shimada Yuichi J. , Raita Yoshihiko , Liang Lusha W. , Maurer Mathew S. , Hasegawa Kohei , Fifer Michael A. , Reilly Muredach P.
Published: July 2021

Background:

Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM.

Methods:

We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive.

Results:

The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83–0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis—for example, the TGF (transforming growth factor)-β pathway—were also upregulated.

Conclusions:

This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.
Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease
Authors: Schunk Stefan J. , Triem Sarah , Schmit David , Zewinger Stephen , Sarakpi Tamim , Becker Ellen , Hütter Gregor , Wrublewsky Selina , Küting Fabienne , Hohl Mathias , Alansary Dalia , Prates Roma Leticia , Lipp Peter , Möllmann Julia , Lehrke Michael , Laschke Matthias W. , Menger Michael D. , Kramann Rafael , Boor Peter , Jahnen-Dechent Willi , März Winfried , Böhm Michael , Laufs Ulrich , Niemeyer Barbara A. , Fliser Danilo , Ampofo Emmanuel , Speer Thimoteus
Published: July 2021

Background:

Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD.

Methods:

We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in
Il1a
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mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells.

Results:

IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice.

Conclusions:

IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.
Stoma and intestine ultrastructure of the marine free-living nematode Odontophora deconincki (Nematoda: Araeolaimida: Axonolaimidae)
Authors: Fedyaeva Maria A. , Tchesunov Alexei V.
Published: July 2021

The fine morphology of the buccal capsule and intestine (midgut) of the marine free-living nematode Odontophora deconincki was investigated. The cheilostome is armed with six equal claw-like odontia that can evert radially by opening the mouth. Light-refracting accessory buccal structures within the cheilostomatal cuticle alternate with odontia and consist of two elements: anterior armilloids and posterior granular armilliths. The buccal cavity (pharyngostome) is surrounded by a complex of longitudinal and oblique muscles partially attached to the cheilostome cuticle at the sites of the accessory buccal structures and enabling a wide opening of the mouth. With the described stoma condition, the nematode probably scrapes food particles from the substrate surface. In cross-section, the midgut consists of 5-7 cells that appear uniform throughout its length. An extracellular matrix (glycocalyx) over the microvillar brush varies in thickness and stratification depending on presence or absence of food content in the lumen. Abundant spherocrystals (globular inclusions with concentric striations) were present in all gut cells. No indication of endocytosis or digestive vacuoles was observed in the gut cells and extracellular digestion predominates. Most specimens had a gut content formed from a long cylinder of compressed flocculent material with some barely identifiable components and few spherocrystals expelled from the enterocytes. We assume that the nematode diet comprises a wide range of objects, mainly eukariotic epigrowth organisms, which are shorn off and scraped from the surface of sand grains and then ingested.
Lutherans and Pentecostals in Dialogue
Authors: Grenholm Cristina , Habib Zeiler Johannes , Josefsson Ulrik
Published: July 2021

This article provides an analysis of the ongoing ecumenical conversation between Lutherans and Pentecostals in Sweden. The material used in the article consists of written documents combined with references to the experiences from the participants in the dialogue. The aim of the article is threefold: first, to describe the setting, development, and character of the conversation; second, to analyze the contents of the conversation with a focus on the theme of pneumatology; and third, to relate this analysis to the ongoing international Lutheran-Pentecostal dialogue. A theoretical reference point is the growing field of receptive ecumenism, which is described as a third way of ecumenism. One result from this study is that more consensus is reached in areas of societal ministry and advocacy than concerning doctrinal issues. The analysis shows deep ecumenical ambitions built on trust but also reveals some difficulties on the path toward Christian unity.
Development Stages of Islamic Movements in the Pashtun Tribal Environment: The Case of the Rawshaniyya and Beyond
Authors: Andreyev Sergei
Published: July 2021

The Rawshani movement is the first well-documented example of supra-tribal unification and subsequent successful integration of the movement’s leaders into the alien state structures. But by no means is it an isolated phenomenon in Pashtun history. Similar pattern of religion-motivated supra-tribal unification, which should be considered as a product of historical relationships of power, remerged inter alia during more recent crises in the Afghan history. Due to the volatile nature of the Afghan state fluctuating between tribalism and ethnic pluralistic participation, military and Islamic dimensions have always been of paramount importance for state-community relations where religion, tribalism and ethnicity were often the means of state’s control of social resistance and its vehicles. In the time of crises, religion-inspired militia-type independent military formations were able to challenge the might of the state and occasionally even initiate the incipient state formation opposed to the communal institutions and those of the old regime. When this community-based military activity went beyond the scope of traditional annual cycle of violence it often acquired a supra-tribal or ethnic and regional dimension, which was legitimised by the Islamic ideology and institutions.

This article offers some directions towards making a calibration tool or even identifying a pattern that may be used as an epistemological paradigm that may provide a sense of orientation and bearing in the intricacies of a complex historical interaction between Pashtun Islam, tribes and state.
Reconnecting Forward: Nasjonal Samling’s Apocalyptic Temporality as a Key to the Fascist Regime of Historicity
Authors: Wilhelmsen Fredrik
Published: July 2021

This article analyses the conception of history or ‘regime of historicity’ structuring the ideology of the Norwegian fascist party, Nasjonal Samling (1933–1945). It highlights the value of the theory of palingenetic ultranationalism to the understanding of fascist temporality generically and specifically. Generically, because the findings show how Nasjonal Samling’s regime of historicity followed the same structure of revolution and eternity, decay and rebirth, as other fascist movements did. Specifically, because it also shows how Nasjonal Samling drew heavily on Norwegian national myths. The ideologues of ns recoded these myths, and integrated them into their own palingenetic, apocalyptic, and – after 1935 – antisemitic grand narratives. These crystallized in a triadic scheme, forming a fascist regime of historicity, structured around the myth of past greatness, followed by decadence, combined with a fantasy of a future revolutionary rebirth of the nation.
“People are gazing” — An Interpretative Phenomenological Analysis of Viewing Velázquez
Authors: Starr Rachel A. , Smith Jonathan A.
Published: July 2021

What is it like to look at a painting? Research into art viewing raises challenging considerations. Factors concerning the artwork, the viewer, the role of context, as well as conceptualisation of the response and how to measure it, present a wealth of complexity. Although such a topic might arguably lend itself to qualitative exploration, work of this type is notably sparse. In the research reported here, Interpretative Phenomenological Analysis was used to explore the experience of looking at a painting. Twelve participants were individually interviewed whilst viewing Las Meninas by Diego Velázquez. Three Master Themes were developed, the first of which, ‘The Gaze’, is presented in depth. Experiences of looking and being looked at by figures in the image are described and considered in relation to social and philosophical understandings of eye contact, seeing and being seen.
History of Medicine in Eastern Europe: Sexual Medicine and Women’s Reproductive Health in Czechoslovakia, Poland, and Hungary
Authors: Lišková Kateřina
Published: July 2021

Specific developments in reproductive health occurred in Eastern Europe, especially in the second half of the twentieth century. During state socialism, it was experts, not social movements, who furthered the agenda of women’s health and sexuality. New analyses from the region and written mostly by authors who speak the local languages attest to the wealth of histories, highlighting different timelines of reproductive health developments, the unexpected causes behind them, and the social actors and institutions which played decisive roles.
Thalictrum bouffordii (Ranunculaceae), a new species from the Qionglai mountains region in western Sichuan, China
Authors: ZENG YOU-PAI , YUAN QIONG , YANG QIN-ER
Published: July 2021

Thalictrum bouffordii (Ranunculaceae), a new species from the Qionglai mountains region in western Sichuan, China, is illustrated and described. Morphologically T. bouffordii is most closely similar to T. xinningense in habit and having clavate filaments, apically recurved styles, and sessile, profoundly ribbed and pubescent achenes, but differs by having proximally glabrous (vs. densely pubescent) stem, inflorescence a many-flowered corymbiform compound monochasium (vs. a thyrse), abaxially pubescent (vs. glabrous) sepals, and purplish (vs. white) filaments.
Novelties in Begonia (Begoniaceae) from the campos rupestres of Serra do Padre Ângelo, Minas Gerais, Brazil: a new species and a new record
Authors: KOLLMANN LUDOVIC JEAN CHARLES , GONELLA PAULO MINATEL
Published: July 2021

Begonia piranga (Begoniaceae) is a new narrowly endemic species from the campos rupestres of Serra do Padre Ângelo, a quartzitic massif in Conselheiro Pena, eastern Minas Gerais state, Brazil. Description, diagnosis, taxonomic comments, detailed illustrations, field photographs, and a provisional IUCN Red List Assessment are provided. The new species is considered Critically Endangered due to its restricted occurrence in high elevation rock outcrops, small population size, and decline in the quality of the habitat. Begonia vasconcelosiana, another Critically Endangered species, is also newly reported here for Serra do Padre Ângelo. These discoveries add to the increasing list of novelties from Serra do Padre Ângelo, reinforcing the urge for conservation actions to protect the endemic flora of this Serra and other areas of campos rupestres in eastern Minas Gerais state.
The impacts of cloud-radiative changes on poleward atmospheric and oceanic energy transport in a warmer climate
Authors: Chen Yong-Jhih , Hwang Yen-Ting , Ceppi Paulo
Published: July 2021

Based on theory and climate model experiments, previous studies suggest most of the uncertainties in projected future changes in meridional energy transport and zonal mean surface temperature can be attributed to cloud feedback. To investigate how radiative and dynamical adjustments modify the influence of cloud-radiative changes on energy transport, this study applies a cloud-locking technique in a fully-coupled climate model, CESM. Under global warming, the impacts of cloud-radiative changes on the meridional energy transport are asymmetric in the two hemispheres. In the Northern Hemisphere, the cloud-radiative changes have little impact on energy transport, because 89% of the cloud-induced heating is balanced locally by increasing outgoing longwave radiation. In the Southern Hemisphere, on the other hand, cloud-induced dynamical changes in the atmosphere and the ocean cause enhanced poleward energy transport, accounting for most of the increase in energy transport under warming. Our experiments highlight that the local longwave radiation adjustment induced by temperature variation can partially offset the impacts of cloud-radiative changes on energy transport, making the estimated impacts smaller than those obtained from directly integrating cloud-radiative changes in previous studies. It is also demonstrated that the cloud-radiative impacts on temperature and energy transport can be significantly modulated by the oceanic circulation, suggesting the necessity of considering atmospheric-oceanic coupling when estimating the impacts of cloud-radiative changes on the climate system.
Wintertime precipitation over the Australian Snowy Mountains: Observations from an Intensive Field Campaign 2018
Authors: Ackermann Luis , Huang Yi , Siems Steven , Manton Michael , Lang Francisco , Chubb Thomas , Peace Andrew , Speirs Johanna , Suzanne Kenyon , Protat Alain , Alexander Simon P.
Published: July 2021

Understanding the key dynamical and microphysical mechanisms driving precipitation in the Snowy Mountains region of southeast Australia, including the role of orography, can help improve precipitation forecasts, which is of great value for efficient water management. An intensive observation campaign was carried out during the 2018 austral winter, providing a comprehensive range of ground-based observations across the Snowy Mountains. We used data from three vertically pointing rain radars, cloud radar, a PARSIVEL disdrometer, and a network of 76 pluviometers. The observations reveal that all of the precipitation events were associated with cold front passages. About half accumulated during the frontal passage associated with deep, fully glaciated cloud tops; while the rest occurred in the post-frontal environment and was associated with clouds with supercooled liquid water (SLW) tops. About three quarters of the accumulated precipitation were observed under blocked conditions, likely associated with blocked stratiform orographic enhancement. Specifically, more than a third of the precipitation resulted from moist cloudless air being lifted over stagnant air, upwind from the barrier, creating SLW-top clouds. These SLW-clouds then produced stratiform precipitation mostly over the upwind slopes and mountain tops, with hydrometeors reaching the mountain tops mostly as rimed snow. Two precipitation events were studied in detail, which showed that during unblocked conditions, orographic convection invigoration and unblocked stratiform enhancement were the two main mechanisms driving the precipitation; with the latter being more prevalent after the frontal passage. During these events, ice particle growth was likely dominated by vapor deposition and aggregation during the frontal periods, while riming dominated during the post-frontal periods.
Momentum Governors of California Undercurrent Transport
Authors: Chen Ru , McWilliams James C. , Renault Lionel
Published: July 2021

The California Undercurrent (CUC) transport, with significant variability ranging from weeks to decades, has consequences for both the climate and biogeochemistry of the California Current system. This study evaluates the governors of the CUC transport and its temporal variability from a momentum perspective, using a mesoscale-resolving regional model. From a 16-yr mean perspective, the along-isobath pressure gradient acts to accelerate the CUC, whereas eddy advection retards it. The topographic form stress, which is part of the volume integrated along-isobath pressure gradient, not only acts in the direction of the time-mean CUC, but also greatly modulates the temporal variability of the CUC transport. This temporal variability is also correlated with the eddy momentum advection. The eddy stress plays a role in transferring both the equatorward wind stress and poleward CUC momentum downward. A theory is formulated to show that, in addition to the conventional vertical redistribution of momentum, the eddy stress can also redistribute momentum horizontally in the area where the correlation between the pressure anomaly and isopycnal fluctuations has large spatial variability.
The Effects of Extreme High Temperature Day-Off on Electricity Conservation
Authors: Su Yu-Wen
Published: July 2021

The continuously increasing temperatures worldwide indicate the frequently extreme heat in summer will become a new normal. The extreme high temperature (EHT) could be dangerous to human health, especially for outdoor workers or commuters, and increase the risk of grid collapse. Thus, the possibility of a day-off due to EHT has started to be discussed in Taiwan, based on the experience of typhoon day-off, but not yet concluded. In this study, the effects of the EHT day-off on electricity consumption in the industrial, service, and residential sectors was investigated through two determinants: First, high temperature would increase the electricity consumption in space cooling. Second, a day-off would change people’s behavior of electricity consumption from workday to non-workday modes. Combining the effects of cooling hours and non-workdays, the net influence of the EHT day-off on electricity consumption can be evaluated. Estimated results indicated that an EHT day-off can reduce aggregate electricity consumption by between 0.41% and 1.08%. The reduction of electricity consumption due to the off-day offsets the increase driven by high temperatures. Thus, an EHT day-off will mitigate the pressure of power grid and be of benefit to electricity conservation.