bluuebunny/crossref_metadata_2025 huggingface dataset:
Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma
Authors: Dmello Crismita , Sonabend Aarón , Arrieta Victor A. , Zhang Daniel Y. , Kanojia Deepak , Chen Li , Gould Andrew , Zhang Jiangshan , Kang Seong Jae , Winter Jan , Horbinski Craig , Amidei Christina , Győrffy Balázs , Cordero Alex , Chang Catalina Lee , Castro Brandyn , Hsu Patrick , Ahmed Atique U. , Lesniak Maciej S. , Stupp Roger , Sonabend Adam M.
Published: May 2022

Purpose:

Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood–brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy.

Experimental Design:

To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knockout (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival.

Results:

Combination of CRISPR screen results with outcomes from patients with taxane-treated breast cancer led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells, and in multiple intracranial glioma xenografts models. KO of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α.

Conclusions:

Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.
Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration-Resistant Prostate Cancer
Authors: Coleman Ilsa M. , DeSarkar Navonil , Morrissey Colm , Xin Li , Roudier Martine P. , Sayar Erolcan , Li Dapei , Corey Eva , Haffner Michael C. , Nelson Peter S.
Published: May 2022

Purpose:

To determine whether metastatic castration–resistant prostate cancers (mCRPC) partition into molecular phenotypes corresponding to intrinsic differentiation states and ascertain whether these subtypes exhibit specific druggable features and associate with treatment outcomes.

Experimental Design:

We used RNAseq, digital spatial profiling, and histological assessments from metastatic biopsies and patient-derived xenografts to segregate mCRPCs into subtypes defined by the PAM50 breast cancer classification algorithm. Subtype associations with treatment responses in preclinical models and patients were determined.

Results:

Using the PAM50 algorithm, we partitioned 270 mCRPC tumors into LumA (42%), LumB (24%), and Basal (34%) subtypes with classification largely driven by proliferation rates and androgen receptor (AR) activity. Most neuroendocrine tumors classified as Basal. Pathways enriched in the LumA subtype include TGFß and NOTCH signaling. LumB subtype tumors were notable for elevated MYC activity. Basal subtype tumors exhibited elevated IL6-STAT3 signaling and features of adult stem cell states. In patients where multiple tumors were evaluated, the majority had concordant PAM50 subtype determination, though a subset exhibited marked inter- and intratumor heterogeneity, including divergent classifications between primary and metastatic sites. In preclinical models, LumA subtype tumors were highly responsive to androgen deprivation and docetaxel chemotherapy whereas Basal tumors were largely resistant. In clinical cohorts patients with Basal subtype tumors demonstrated a shorter time on treatment with AR signaling inhibitors and docetaxel relative to patients with luminal subtypes.

Conclusions:

Subtyping of mCRPC based on cell differentiation states has potential clinical utility for identifying patients with divergent expression of treatment targets and responses to systemic therapy.
Genomic Analysis of a Spontaneous Model of Breast Cancer Metastasis to Bone Reveals a Role for the Extracellular Matrix
Authors: Eckhardt Bedrich L. , Parker Belinda S. , van Laar Ryan K. , Restall Christina M. , Natoli Anthony L. , Tavaria Michael D. , Stanley Kym L. , Sloan Erica K. , Moseley Jane M. , Anderson Robin L.
Published: May 2022

A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.
Bone Morphogenetic Protein-2 Stimulates Angiogenesis in Developing Tumors
Authors: Langenfeld Elaine M. , Langenfeld John
Published: May 2022

Bone Morphogenetic Protein-2 (BMP-2) is highly overexpressed in the majority of patient-derived lung carcinomas. However, a mechanism revealing its role in cancer has not been established. Here we report that BMP-2 enhances the neovascularization of developing tumors. Recombinant BMP-2 stimulated blood vessel formation in tumors formed from A549 cells injected s.c. into thymic nude mice. Recombinant BMP-2 also enhanced angiogenesis in Matrigel plugs containing A549 cells in nude mice. The BMP-2 antagonist noggin abrogated BMP-2-induced angiogenic response. Furthermore, antisense transfection of BMP-2 cDNA resulted in a decrease in blood vessel formation in the Matrigel assays. BMP-2 induced tube formation in both human aortic endothelial cells (HAEC) and umbilical vein endothelial cells. BMP-2 also stimulated proliferation of HAEC. The ability of BMP-2 to activate endothelial cells was further demonstrated by its ability to phosphorylate Smad 1/5/8 and ERK-1/2 and to increase expression of Id1. This study reveals that BMP-2 enhanced the angiogenic response in developing tumors. Furthermore, these data suggest that BMP-2 stimulation of angiogenesis may involve the activation of endothelial cells.
Nucleosomes Bind Fibroblast Growth Factor-2 for Increased Angiogenesis In vitro and In vivo
Authors: Tanner Jerome E. , Forté André , Panchal Chandra
Published: May 2022

Solid tumors often display sites of necrosis near regions of angiogenesis in vivo. As tumor cell necrosis would result in the release of nucleosomes into the extracellular environment, we explored the potential role of nucleosomes in the promotion of angiogenesis. Data indicate that nucleosomes acted similar to heparin and bound to several heparin-binding, proangiogenic factors [i.e., fibroblast growth factor (FGF)-1, FGF-2, vascular endothelial growth factor, and transforming growth factor-β1]. Nucleosomes modestly enhanced FGF-2 growth of human umbilical vein endothelial cells when grown in restricted media as well as increased human umbilical vein endothelial cell migration and primitive blood vessel tube formation in vitro. On s.c. injection in mice, nucleosomes aided FGF-2 in promoting angiogenesis. These results suggest that nucleosomes released from dying tumor cells aid in the formation of blood vessels and may provide a novel means by which tumor cells increase angiogenesis.
Involvement of the Chemokine Receptor CXCR4 and Its Ligand Stromal Cell-Derived Factor 1α in Breast Cancer Cell Migration Through Human Brain Microvascular Endothelial Cells
Authors: Lee Byeong-Chel , Lee Tae-Hee , Avraham Shalom , Avraham Hava Karsenty
Published: May 2022

In this study, we have characterized the signaling pathways mediated by CXCR4 in breast cancer cells and its role in breast cancer cell invasion and migration. Stromal cell-derived factor 1α (SDF-1α; CXCL12) stimulation of breast cancer cells resulted in phosphoinositide 3-kinase (PI-3K) activation, AKT phosphorylation, and activation of the FKHRL1 transcription factor. In addition, SDF-1α induced activation of the focal adhesion kinase (FAK) as well as the migration of breast cancer cells. Expression of SDF-1α, the ligand of CXCR4, was about 2-fold higher in microdissected human breast epithelial cancer cells as compared with normal epithelial cells. Immunohistochemical analysis indicated that SDF-1α expression is consistently higher in primary breast tumor cells than in normal breast epithelial cells. Furthermore, SDF-1α induced blood vessel instability, through increased vascular permeability, resulting in the penetration of breast tumor cells through the human brain microvascular endothelial cells (HBMEC). Notably, the migration of breast cancer cells was inhibited by the PI-3K inhibitor, Wortmannin, and the Ca2+ inhibitor BAPTA/AM, indicating that transendothelial breast cancer cell migration induced by SDF-1α is mediated by activation of the PI-3K/AKT pathway and Ca2+-mediated signaling. Blockade of the CXCR4/SDF1 signaling pathway with anti-CXCR4 antibody also decreased transendothelial breast cancer cell migration as well as vascular permeability. This study focuses on novel interactions between highly relevant signaling pathways in breast cancer cells and brain microvascular endothelial cells and may provide insights into the molecular mechanisms of CXCR4/SDF-1α-mediated breast cancer metastasis to the brain.
Vascular Remodeling Marks Tumors That Recur During Chronic Suppression of Angiogenesis
Authors: Huang Jianzhong , Soffer Samuel Z. , Kim Eugene S. , McCrudden Kimberly W. , Huang Joe , New Tamara , Manley Christina A. , Middlesworth William , O'Toole Kathleen , Yamashiro Darrell J. , Kandel Jessica J.
Published: May 2022

The potential for avoiding acquired resistance to therapy has been proposed as one compelling theoretical advantage of antiangiogenic therapy based on the normal genetic status of the target vasculature. However, previous work has demonstrated that tumors may resume growth after initial inhibition if antiangiogenic blockade is continued for an extended period. The mechanisms of this recurrent growth are unclear. In these studies, we characterized molecular changes in vasculature during apparent resumption of xenograft growth after initial inhibition by vascular endothelial growth factor blockade, “metronome” topotecan chemotherapy, and combined agents in a xenograft murine model of human Wilms' tumor. Tumors that grew during antiangiogenic blockade developed as viable clusters surrounding strikingly remodeled vessels. These vessels displayed significant increases in diameter and active proliferation of vascular mural cells and expressed platelet-derived growth factor-B, a factor that functions to enhance vascular integrity via stromal cell recruitment. In addition, remodeled vessels were marked by expression of ephrinB2, required for proper assembly of stromal cells into vasculature. Thus, enhanced vascular stability appears to characterize tumor vessel response to chronic antiangiogenesis, features that potentially support increased perfusion and recurrent tumor growth.
Activation of Proteinase-Activated Receptor 1 Promotes Human Colon Cancer Cell Proliferation Through Epidermal Growth Factor Receptor Transactivation
Authors: Darmoul Dalila , Gratio Valérie , Devaud Hélène , Peiretti Franck , Laburthe Marc
Published: May 2022

Serine proteases are now considered as crucial contributors to the development of human colon cancer. We have shown recently that thrombin is a potent growth factor for colon cancer cells through activation of the aberrantly expressed protease-activated receptor 1 (PAR1). Here, we analyzed the signaling pathways downstream of PAR1 activation, which lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events on activation of PAR1 by thrombin or specific activating peptide: (a) a matrix metalloproteinase–dependent release of transforming growth factor-α (TGF-α) as shown with TGF-α blocking antibodies and measurement of TGF-α in culture medium; (b) TGF-α-mediated activation of epidermal growth factor receptor (EGFR) and subsequent EGFR phosphorylation; and (c) activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and subsequent cell proliferation. The links between these events are shown by the fact that stimulation of cell proliferation and ERK1/2 on activation of PAR1 is reversed by the MMP inhibitor batimastat, TGF-α neutralizing antibodies, EGFR ligand binding domain blocking antibodies, and the EGFR tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGFR seems to be a major mechanism whereby activation of PAR1 results in colon cancer cell growth. Finally, PAR1 activation induces Src phosphorylation, which is reversed by using the Src tyrosine kinase inhibitor PP2, suggesting that Src activation plays a permissive role for PAR1-mediated ERK1/2 activation and cell proliferation probably acting downstream of the EGFR. These data explain how thrombin exerts robust trophic action on colon cancer cells and underline the critical role of EGFR transactivation.
Development of Head and Neck Squamous Cell Carcinoma Is Associated With Altered Cytokine Responsiveness
Authors: Douglas Wade G. , Tracy Erin , Tan Dongfeng , Yu Jihnhee , Hicks Jr. Wesley L. , Rigual Nestor R. , Loree Thom R. , Wang Yanping , Baumann Heinz
Published: May 2022

Growth of head and neck squamous cell carcinoma (HNSCC) is generally associated with an inflammatory component. It is hypothesized that these tumor cells develop mechanisms to evade the growth inhibitory effects of cytokines that are present in the tumor microenvironment. This study determined the changes in responsiveness to inflammatory cytokines that accompany the transition of normal to transformed epithelial cells. Paired primary cultures of normal epithelial cells (NEC) and SCC cells were established from 16 patients. Receptor-mediated activation of signal transducer and activator of transcription and extracellular signal-regulated kinase pathways in response to cytokine treatments was identified by immunoblot analysis. Thymidine incorporation determined the impact of the cytokines on DNA synthesis. HNNEC and HNSCC displayed a prominent signaling in response to oncostatin M, interleukin-6, IFN-γ, and epidermal growth factor. Untreated HNSCC showed an elevated level of phosphorylated signal transducer and activator of transcription 3 and extracellular signal-regulated kinase (P < 0.001) compared with HNNEC, suggesting constitutively activated pathways. Moreover, HNSCC cells phosphorylated significantly more signal transducer and activator of transcription 1 in response to oncostatin M (P = 0.002) and IFN-γ (P = 0.018) treatments. DNA synthesis of SCC cells was less inhibited by cytokines produced by endotoxin-stimulated macrophages (P = 0.016) than that of NEC. Low-dose oncostatin M slightly enhanced proliferation of SCC, whereas that of NEC was suppressed (P = 0.016). This study identified significant alterations in signal transduction pathways engaged by cytokines and which are associated with loss of growth inhibition of HNSCC. Increased signal transducer and activator of transcription phosphorylation, along with constitutively phosphorylated extracellular signal-regulated kinase in HNSCC, suggest that these pathways as molecular markers are important in the malignant transformation process and are potential targets for treatment.
Transforming Potential of Alternatively Spliced Variants of Fibroblast Growth Factor Receptor 2 in Human Mammary Epithelial Cells
Authors: Moffa Allison B. , Tannheimer Stacey L. , Ethier Stephen P.
Published: May 2022

A breast cancer cell line developed in our laboratory (SUM-52PE) has a 12-fold amplification and high-level overexpression of the oncogene fibroblast growth factor receptor 2 (FGFR2). Previously, nine different alternatively spliced FGFR2 variants were isolated from this cell line. Overexpression of two variants that differ only in their carboxyl termini (C1 and C3) has been successfully accomplished in the immortalized human mammary epithelial cell line H16N2. FGFR2 expression led to the activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling cascades. Phosphorylation of the adapter protein FGF receptor substrate 2 is much more robust in the cells expressing the C3 variant of FGFR2 compared with the C1 variant. H16N2 cells expressing the full-length FGFR2 with the C1 or C3 carboxyl terminus were tested for their ability to grow under epidermal growth factor (EGF)–independent conditions, in soft agar, and for their ability to invade naturally occurring basement membranes and compared with the parental SUM-52PE cell line. All three cell lines grew under EGF-independent conditions and all were inhibited by the FGFR family specific inhibitor PD173074. The full-length FGFR2-C1 and FGFR2-C3 variants grew robustly in soft agar similar to the parental cell line SUM-52PE. However, cells expressing the C3 variant formed large colonies in agar in both insulin-free and EGF-free medium, whereas the cells expressing the C1 variant required insulin for growth. Soft agar growth was also inhibited by PD173074. Because SUM-52PE was developed from a metastatic breast carcinoma, the FGFR2-overexpressing cell lines were assessed for their ability to invade sea urchin embryo cell membranes. H16N2 cells expressing the C1 carboxyl terminus failed to invade sea urchin embryo cell membranes. By contrast, FGFR2-C3-expressing cells were as invasive as the SUM-52 breast cancer cells and erbB-2-overexpressing H16N2 cells. These results indicate that FGFR2 is a transforming oncogene in human mammary epithelial cells when expressed to levels similar to that found in breast cancer cells with FGFR2 gene amplification. Furthermore, the results suggest that different splice variants have differing transforming activities and that signaling from variants expressing the C3 carboxyl terminus results in more autonomous signaling, cell growth, and invasion.
Inhibition of Hypoxia-Inducible Factor Is Sufficient for Growth Suppression of VHL−/− Tumors
Authors: Zimmer Michael , Doucette Darrell , Siddiqui Naila , Iliopoulos Othon
Published: May 2022

The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate receptor for the mammalian SCF-2 E3 ubiquitin ligase complex that targets several substrates for ubiquitination and proteasomal degradation. Among these targets are the α-regulatory subunits of the hypoxia-inducible factor (HIF). VHL−/− cells constitutively overexpress hypoxia-inducible genes through both transcriptional and posttranscriptional mechanisms and form tumors when injected into nude mice. Reintroduction of pVHL into VHL−/− cell lines restores normal oxygen-dependent regulation of these genes and suppresses tumor formation in the mouse xenograft assay. We report here that short hairpin RNA-mediated inactivation of HIF phenocopies the effects of pVHL reintroduction with respect to decreased expression of hypoxia-inducible genes, decreased ability to promote vascular endothelial cell proliferation in vitro, and tumor growth suppression in vivo. In addition, HIF inactivation abrogated the cellular response to hypoxia, indicating that HIF is the only pVHL target required for this response. These data suggest that deregulation of hypoxia-inducible genes in VHL−/− cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target.
Efficient Down-Regulation of Cyclin A-Associated Activity and Expression in Suspended Primary Keratinocytes Requires p21Cip1
Authors: Hauser Paul , Ma Le , Agrawal Deepak , Haura Eric , Cress W. Douglas , Pledger W. Jackson
Published: May 2022

When suspended in methylcellulose, primary mouse keratinocytes cease proliferation and differentiate. Suspension also reduces the activity of the cyclin-dependent kinase cdk2, an important cell cycle regulatory enzyme. To determine how suspension modulates these events, we examined its effects on wild-type keratinocytes and keratinocytes nullizygous for the cdk2 inhibitor p21Cip1. After suspension of cycling cells, amounts of cyclin A (a cdk2 partner), cyclin A mRNA, and cyclin A-associated activity decreased much more rapidly in the presence than in the absence of p21Cip1. Neither suspension nor p21Cip1 status affected the stability of cyclin A mRNA. Loss of p21Cip1 reduced the capacity of suspended cells to growth arrest, differentiate, and accumulate p27Kip1 (a second cdk2 inhibitor) and affected the composition of E2F DNA binding complexes. Cyclin A-cdk2 complexes in suspended p21+/+ cells contained p21Cip1 or p27Kip1, whereas most of the cyclin A-cdk2 complexes in p21−/− cells lacked p27Kip1. Ectopic expression of p21Cip1 allowed p21−/− keratinocytes to efficiently down-regulate cyclin A and differentiate when placed in suspension. These findings show that p21Cip1 mediates the effects of suspension on numerous processes in primary keratinocytes including cdk2 activity, cyclin A expression, cell cycle progression, and differentiation.
Das Schlafapnoe-Syndrom und die Auswirkungen auf das Auge
Authors: Göbel Katja
Published: May 2022

Obstructive sleep apnea (OSA), the most common form of sleep-disordered breathing, is characterized by repetitive episodes of paused breathing during sleep, which in turn induces transient nocturnal hypoxia and hypercapnia. The high prevalence of OSA and its associated health consequences place a heavy burden on the healthcare system. In particular, the consequent episodic oxy­genic desaturation/reoxygenation series and arousals from sleep in patients with OSA have the potential to trigger oxidative stress, elevated systemic inflammatory responses, and autonomic dysfunction with sympathetic activation. Given these adverse side-effects, OSA is highly correlated to many eye diseases that are common in everyday ophthalmic practices. Some of these ocular consequences are reversible, but they may permanently threaten a patient’s vision if not treated appropriately. Here, this article seeks to review the ocular consequences and potential pathophysiologic associations in patients with OSA. Understanding these OSA-related eye diseases may help clinicians provide comprehensive care to their patients.
Cerebrovascular Disease Profiles of Culturally and Linguistically Diverse Communities in South Western Sydney and New South Wales
Authors: Cordato Dennis , Blair Christopher , Thomas Peter , Firtko Angela , Miller Megan , Edwards Leon Stephen , Thomas James , Balabanski Anna H. , Dos Santos Angela , Lin Longting , Hodgkinson Suzanne , Cappelen-Smith Cecilia , Beran Roy G. , McDougall Alan , Parsons Mark
Published: May 2022

Introduction: Culturally and linguistically diverse (CALD) communities are growing globally. Understanding patterns of cerebrovascular disease in CALD communities may improve health outcomes through culturally specific interventions. We compared rates of transient ischaemic attack (TIA)/stroke (ischaemic stroke, intracerebral haemorrhage) and stroke risk factor prevalence in overseas and Australian-born people in South Western Sydney (SWS) and New South Wales (NSW). Methods: This was a 10-year retrospective analysis (2011–2020) of SWS and NSW age-standardized rates per 100,000 person-years of TIA/stroke. Data were extracted from Health Information Exchange and Secure Analytics for Population Health Research and Intelligence systems. Rates of hypertension, type 2 diabetes mellitus (T2DM), atrial fibrillation (AF), smoking, and obesity were also calculated. Results: The SWS and NSW age-standardized rate of TIA/stroke for people born in Australia was 100 per 100,000 person-years (100/100,000/year). In SWS, 56.6% of people were overseas-born compared to 29.8% for NSW. The age-standardized rate of TIA/stroke for Polynesian-born people was more than double that of Australian-born people (p < 0.001). Hypertension (33 [SWS] vs. 27/100,000/year [NSW]) and T2DM (36 [SWS] vs. 26/100,000/year [NSW]) were the most common risk factors with rates >50/100,000/year (hypertension) and >80/100,000/year (T2DM) for people born in Polynesia, Melanesia, and Central America. Rates of T2DM, AF, and obesity for Polynesian-born people were over threefold greater than people born in Australia. Discussion/Conclusion: Greater rates of TIA/stroke were observed in specific CALD communities, with increased rates of cerebrovascular risk factors. Culturally specific, targeted interventions may bridge health inequalities in cerebrovascular disease.
Extended-Release Calcifediol Effectively Raises Serum Total 25-Hydroxyvitamin D Even in Overweight Nondialysis Chronic Kidney Disease Patients with Secondary Hyperparathyroidism
Authors: Bishop Charles W. , Strugnell Stephen A. , Csomor Philipp , Kaiser Edelgard , Ashfaq Akhtar
Published: May 2022

Introduction: Obesity increases the risk of vitamin D insufficiency, which exacerbates secondary hyperparathyroidism in chronic kidney disease. Recent studies suggest that serum total 25-hydroxyvitamin D (25OHD) levels of ≥50 ng/mL are necessary to produce significant reductions in elevated parathyroid hormone levels in nondialysis patients. Data from real-world and randomized controlled trials (RCTs) involving these patients were examined for (1) relationships between vitamin D treatments and the achieved levels of serum 25OHD and between serum 25OHD and body weight (BW)/body mass index (BMI); and (2) the impact of BW/BMI on achieving serum 25OHD levels ≥50 ng/mL with extended-release calcifediol (ERC) treatment or vitamin D supplementation (cholecalciferol or ergocalciferol). Methods: Data obtained from nondialysis patients participating in two real-world studies, one conducted in Europe (Study 1) and the other (Study 2) in the USA, and in two US RCTs (Studies 3 and 4) were analyzed for serum 25OHD outcomes after treatment with ERC, vitamin D supplements, or placebo. Results: More than 50% of subjects treated with vitamin D supplements in both real-world studies (Studies 1 and 2) failed to achieve serum 25OHD levels ≥30 ng/mL, a level widely viewed by nephrologists as the threshold of adequacy; only 7.3–7.5% of subjects achieved levels ≥50 ng/mL. Data from the European study (Study 1) showed that serum 25OHD levels had significant and nearly identical inverse relationships with BW and BMI, indicating that high BW or BMI thwarts the ability of vitamin D supplements to raise serum 25OHD. One RCT (Study 3) showed that 8 weeks of ERC treatment (60 μg/day) raised serum 25OHD levels to ≥30 and 50 ng/mL in all subjects, regardless of BW, while cholecalciferol (300,000 IU/month) raised serum 25OHD to these thresholds in 56% and 0% of subjects, respectively. The other RCT (Study 4) showed that ERC treatment (30 or 60 μg/day) successfully raised mean serum 25OHD levels to at least 50 ng/mL for subjects in all BW categories, whereas no increases were observed with placebo treatment. Conclusion: Real-world studies conducted in Europe and USA in nondialysis patients (Studies 1 and 2) showed that vitamin D supplements (cholecalciferol or ergocalciferol) were unreliable in raising serum total 25OHD to targets of 30 or 50 ng/mL. In contrast, ERC was demonstrated to be effective in one real-world study (Study 2) and two RCTs (Studies 3 and 4) conducted in US nondialysis patients in raising serum 25OHD to these targeted levels irrespective of BW.
Efficiency of Hair Detection in Hair-to-Hair Matched Trichoscopy
Authors: Bokhari Laita , Cottle Phoebe , Grimalt Ramon , Kasprzak Michal , Sicińska Justyna , Sinclair Rodney , Tosti Antonella
Published: May 2022

Introduction: Precise evaluation of changes in hair count is crucial for monitoring progression of hair loss and the effects of treatment. The focus of this study is the comparison of the various examination and assessment techniques in terms of the precision of hair count change observed in trichoscopy images. Methods: Controlled hair extraction of the same scalp spot was used to simulate hair loss, and the different examination techniques were performed to detect this change. The investigators who performed the counting were blinded. Results: For trichoscopy images, the average error in determining the terminal hair count change (relative to total hair count) was 9 ± 1% for automatic assessment with manual correction and 0.4 ± 0.2% for hair-to-hair matched images. For phototrichogram, the automatic measurement results were found to deviate from truth on average by 12 ± 2%. The manually corrected hair count results were much closer to the truth with average deviation at the level of 7 ± 1%. The hair-to-hair matched results corresponded to approximately 0.6 ± 0.3% average discrepancy. Conclusion: Combination of manually corrected image processing, follicular mapping, and hair-to-hair matching appears to be the most precise way of evaluating the change in hair count over time. These novel techniques should be considered valuable, especially in research and clinical trials.
Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
Authors: Gytz Olesen Heidi , Michailidou Iliana , Zelek Wioleta M. , Vreijling Jeroen , Ruizendaal Patrick , de Klein Ferry , Marquart J. Arnoud , Kuipers Thomas B. , Mei Hailiang , Zhang Yuchun , Ahasan Muhammad , Johnson Krista K. , Wang Yi , Morgan B. Paul , van Dijk Marcus , Fluiter Kees , Andersen Gregers Rom , Baas Frank
Published: May 2022

Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement component C6 showed improved recovery after neuronal trauma. Thus, inhibitors of the MAC might be of therapeutic use in neurological disease. Here, we describe the development, structure, mode of action, and properties of a novel therapeutic monoclonal antibody, CP010, against C6 that prevents formation of the MAC in vivo. The monoclonal antibody is humanized and specific for C6 and binds to an epitope in the FIM1-2 domain of human and primate C6 with sub-nanomolar affinity. Using biophysical and structural studies, we show that the anti-C6 antibody prevents the interaction between C6 and C5/C5b by blocking the C6 FIM1-2:C5 C345c axis. Systemic administration of the anti-C6 mAb caused complete depletion of free C6 in circulation in transgenic rats expressing human C6 and thereby inhibited MAC formation. The antibody prevented disease in experimental autoimmune myasthenia gravis and ameliorated relapse in chronic relapsing experimental autoimmune encephalomyelitis in human C6 transgenic rats. CP010 is a promising complement C6 inhibitor that prevents MAC formation. Systemic administration of this C6 monoclonal antibody has therapeutic potential in the treatment of neuronal disease.
Deep Learning for Automatic Upper Airway Obstruction Detection by Analysis of Flow-Volume Curve
Authors: Wang Yimin , Li Yicong , Chen Wenya , Zhang Changzheng , Liang Lijuan , Huang Ruibo , Jian Wenhua , Liang Jianling , Zhu Senhua , Tu Dandan , Gao Yi , Zhong Nanshan , Zheng Jinping
Published: May 2022

Background: Due to the similar symptoms of upper airway obstruction to asthma, misdiagnosis is common. Spirometry is a cost-effective screening test for upper airway obstruction and its characteristic patterns involving fixed, variable intrathoracic and extrathoracic lesions. We aimed to develop a deep learning model to detect upper airway obstruction patterns and compared its performance with that of lung function clinicians. Methods: Spirometry records were reviewed to detect the possible condition of airway stenosis. Then they were confirmed by the gold standard (e.g., computed tomography, endoscopy, or clinic diagnosis of upper airway obstruction). Images and indices derived from flow-volume curves were used for training and testing the model. Clinicians determined cases using spirometry records from the test set. The deep learning model evaluated the same data. Results: Of 45,831 patients’ spirometry records, 564 subjects with curves suggesting upper airway obstruction, after verified by the gold standard, 351 patients were confirmed. These cases and another 200 cases without airway stenosis were used as the training and testing sets. 432 clinicians evaluated 20 cases of each of the three patterns and 20 no airway stenosis cases (n = 80). They assigned an accuracy of 41.2% (±15.4) (interquartile range: 27.5–52.5%), with poor agreements (κ = 0.12). For the same cases, the model generated a correct detection of 81.3% (p < 0.0001). Conclusions: Deep learning could detect upper airway obstruction patterns from other classic patterns of ventilatory defects with high accuracy, whereas clinicians presented marked errors and variabilities. The model may serve as a support tool to enhance clinicians’ correct diagnosis of upper airway obstruction using spirometry.
Branching Dilated Vessels: A Possible Trichoscopic Clue for Diagnosis of Erosive Pustular Dermatosis of the Scalp in Children
Authors: Abbenante Diego , Starace Michela V.R. , Leuzzi Miriam , Chessa Marco Adriano , Piraccini Bianca Maria , Neri Iria
Published: May 2022

Introduction: Erosive pustular dermatosis of the scalp (EPDS) is an inflammatory scalp condition that usually affects the elderly, while only few cases have been reported in childhood. In children, it may mimic fungal or bacterial infections, especially kerion. Case Presentation: We describe the usefulness of trichoscopy as a supportive diagnostic tool in 2 cases of pediatric EPDS. Discussion: Clinical distinction between EPDS and different types of alopecia in children is difficult, with a significant likelihood of diagnostic errors and delay in therapy. Trichoscopy may provide a noninvasive option that can help avoid invasive diagnostic procedures in children.
Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis
Authors: Hasegawa Morio , Fukushima Hiroko , Suzuki Ryoko , Yamaki Yuni , Hosaka Sho , Inaba Masako , Nakao Tomohei , Kobayashi Chie , Yoshimi Ai , Tsuchida Masahiro , Koike Kazutoshi , Fukushima Takashi , Takada Hidetoshi
Published: May 2022

Introduction: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. Materials and Methods: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. Results: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. Discussion/Conclusion: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.
Risk Factor Profile in Youth, Genetic Risk, and Adulthood Cognitive Function: The Cardiovascular Risk in Young Finns Study
Authors: Wu Feitong , Ahola-Olli Ari , Pahkala Katja , Hakala Juuso O. , Juonala Markus , Salo Pia , Lehtimäki Terho , Hutri-Kähönen Nina , Kähönen Mika , Laitinen Tomi , Tossavainen Päivi , Taittonen Leena , Jokinen Eero , Viikari Jorma S.A. , Magnussen Costan G. , Raitakari Olli T. , Rovio Suvi P.
Published: May 2022

Introduction: The role of risk factor profile in childhood and adolescence on adulthood cognitive function and whether it differs by genetic risk is still obscure. To bring this evidence, we determined cognitive domain-specific youth risk factor profiles leveraging the childhood/adolescence data from the Cardiovascular Risk in Young Finns Study and examined whether genetic propensity for poor cognitive function modifies the association between the risk profiles and adulthood cognitive function. Methods: From 1980, a population-based cohort of 3,596 children (age 3–18 years) has been repeatedly followed up for 31 years. Computerized cognitive test measuring (1) memory and learning, (2) short-term working memory, (3) reaction time, and (4) information processing was performed for 2,026 participants (age 34–49 years). Cognitive domain-specific youth risk profile scores, including physical and environmental factors, were assessed from the data collected at baseline and categorized into favourable, intermediate, and unfavourable. A polygenic risk score for a poor cognitive function was categorized into low, intermediate, and high risk. Results: At all genetic risk levels, a favourable youth risk factor profile is associated with better learning and memory, short-term working memory, and information processing compared to unfavourable risk profile (e.g., β = 0.501 SD, 95% CI: 0.043–0.959 for memory and learning among participants with high genetic risk). However, no significant interactions were observed between the youth risk factor profile score and genetic propensity for any cognitive domain (p > 0.299 for all). Conclusion: A favourable youth risk factor profile may be beneficial for cognitive function in adulthood, irrespective of genetic propensity for poor cognitive function.
Serum Thyrotropin Elevation and Coronary Artery Calcification in Hemodialysis Patients
Authors: Rhee Connie M. , Budoff Matthew , Brent Gregory , You Amy S. , Stenvinkel Peter , Novoa Alejandra , Flores Ferdinand , Hamal Sajad , Dailing Christopher , Kinninger April , Nakata Tracy , Kovesdy Csaba P. , Nguyen Danh V. , Kalantar-Zadeh Kamyar
Published: May 2022

Introduction: Hypothyroidism is highly prevalent in end-stage kidney disease patients, and emerging data show that lower circulating thyroid hormone levels lead to downregulation of vascular calcification inhibitors and coronary artery calcification (CAC) in this population. To date, no studies have examined the association of serum thyrotropin (TSH), the most sensitive and specific single biochemical metric of thyroid function, with CAC risk in hemodialysis patients. Methods: In secondary analyses of patients from the Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients trial, we examined serum TSH levels and CAC risk assessed by cardiac computed tomography scans collected within a 90-day period. We evaluated the relationship between serum TSH with CAC Volume (VS) and Agatston score (AS) (defined as >100 mm3 and >100 Houndsfield Units, respectively) using multivariable logistic regression. Results: Among 104 patients who met eligibility criteria, higher TSH levels in the highest tertile were associated with moderately elevated CAC VS and AS in case-mix-adjusted analyses (ref: lowest tertile): adjusted ORs (95% CIs) 4.26 (1.18, 15.40) and 5.53 (1.44, 21.30), respectively. TSH levels >3.0 mIU/L (ref: ≤3.0 mIU/L) were also associated with moderately elevated CAC VS and AS. In secondary analyses, point estimates of incrementally lower direct free thyroxine levels trended toward elevated CAC VS and AS, although associations did not achieve statistical significance. Conclusions: In hemodialysis patients, higher serum TSH was associated with elevated CAC VS and AS. Further studies are needed to determine if thyroid hormone supplementation can attenuate CAC burden in this population.
Abstract 157: Clinical And Social Determinants Of Change In Code Status Among Patients Hospitalized With Covid-19
Authors: Ploch Michelle , Ahmed Talha , Reyes Stephan , Irizarry-Caro Jorge A , Fossas-Espinosa Jose E , Shoar Saeed , Amatullah Atia , Safavi-Naeini Payam , Jogimahanti Arjun , Antonioli Matthew , Iliescu Cesar A , Balan Prakash , Madjid Mohammad
Published: May 2022

Background:
Patients hospitalized with COVID-19 who develop cardiopulmonary arrest often have poor prognosis, prompting discussions with families about goals of care. The relationship between clinical and social determinants of code status change is poorly understood.

Methods:
This retrospective study included adult COVID-19 positive patients admitted to the intensive care unit with cardiac arrest in a multihospital center over the first 9 months of the pandemic (3/1/2020 - 12/1/2020). Data on medical and social factors was collected and adjudicated.

Results:
We identified 208 patients over the study timeline. The mean age was 63.7 ± 14.5 years and 54.3% (n=113) were male. The majority of patients with cardiopulmonary arrest had pulseless electrical activity (PEA) as their initial rhythm (91.3%, n=190). Code status was changed in 56.3% (n=117) of patients. The majority of COVID-19 patients with cardiac arrest were Hispanic (53.4%, n=111), followed by African American (27.9%, n=58), and White patients (13.5%, n=28). Race/ethnicity did not affect the rate of code status change. COVID-19 patients who had a code status change were statistically more likely to have a lower salary ($54,838 vs $62,374), have a history of stroke/transient ischemic attack (15.4 vs 4.4%, 18:4), or heart failure (28.2 vs 15.6%, 33:14), all with P<0.05. Patients with code status change had shorter courses of cardiopulmonary resuscitation (11.9 vs 16.9 minutes, P<0.05). Both groups had similar levels of aggressive care received including continuous renal replacement therapy, vasopressor and broad-spectrum antibiotics requirements. Insurance status, ethnicity, religion, and education did not lead to statistically significant changes in code status in COVID patients.

Conclusion:
Patients hospitalized with cardiopulmonary arrest and positive for COVID-19 are more likely to have a change in code status. This code status change is affected by cardiovascular comorbidities such as stroke and heart failure, along with lower income but not by insurance status, ethnicity, religion, and educational level.
Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait
Authors: Wang Yan , Guilliams Kristin P. , Fields Melanie E. , Fellah Slim , Binkley Michael M. , Reis Martin , Vo Katie D. , Chen Yasheng , Ying Chunwei , Blinder Morey , King Allison A. , Hulbert Monica L. , An Hongyu , Lee Jin-Moo , Ford Andria L.
Published: May 2022

Background:

Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function.

Methods:

As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics.

Results:

Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81,
P
=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43,
P
=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g,
P
=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27,
P
=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g,
P
=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL,
P
=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL,
P
=0.053) and correlated with SCI volume (ρ=0.49,
P
=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia.

Conclusions:

Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.