bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Cervical Cancer by Quantitative Promoter Hypermethylation Assay on Cervical Scrapings: A Feasibility Study
Authors: Reesink-Peters Nathalie , Wisman G. Bea A. , Jéronimo Carmen , Tokumaru C. Yutaka , Cohen Yoram , Dong Seung Myung , Klip Harrie G. , Buikema Henk J. , Suurmeijer Albert J.H. , Hollema Harrie , Boezen H. Marieke , Sidransky David , van der Zee Ate G.J.
Published: May 2022

Current morphology-based cervical cancer screening is associated with significant false-positive and false-negative results. Tumor suppressor gene hypermethylation is frequently present in cervical cancer. It is unknown whether a cervical scraping reflects the methylation status of the underlying epithelium, and it is therefore unclear whether quantitative hypermethylation specific PCR (QMSP) on cervical scrapings could be used as a future screening method augmenting the current approach. Cervical scrapings and paired fresh frozen cervical tissue samples were obtained from 53 cervical cancer patients and 45 controls. All scrapings were morphologically scored and analyzed with QMSP for the genes APC, DAPK, MGMT, and GSTP1. To adjust for DNA input, hypermethylation ratios were calculated against DNA levels of a reference gene. Hypermethylation ratios of paired fresh frozen tissue samples and scrapings of cervical cancer patients and controls were strongly related (Spearman correlation coefficient, 0.80 for APC, 0.98 for DAPK, and 0.83 for MGMT; P < 0.001). More cervical cancer patients than controls were DAPK positive (P < 0.001). When cutoff levels for ratios were defined to be above the highest ratio observed in controls, QMSP in cervical scrapings identified 32 (67%) of 48 cervical cancer patients. This feasibility study demonstrates that QMSP on cervical scrapings holds promise as a new diagnostic tool for cervical cancer. The addition of more genes specifically methylated in cervical cancer will further improve the assay.
MDM2 and Its Splice Variant Messenger RNAs: Expression in Tumors and Down-Regulation Using Antisense Oligonucleotides
Authors: Bartel Frank , Harris Linda C. , Würl Peter , Taubert Helge
Published: May 2022

Alternative splicing has an important role in expanding protein diversity. An example of a gene with more than one transcript is the MDM2 oncogene. To date, more than 40 different splice variants have been isolated from both tumor and normal tissues. Here, we review what is known about the alteration of MDM2 mRNA expression, focusing on alternative splicing and potential functions of different MDM2 isoforms. We also discuss the progress that has been made in the development of antisense oligonucleotides targeted to MDM2 for use as a potential cancer therapy.
p63 and p73: Roles in Development and Tumor Formation
Authors: Moll Ute M. , Slade Neda
Published: May 2022

The tumor suppressor p53 is critically important in the cellular damage response and is the founding member of a family of proteins. All three genes regulate cell cycle and apoptosis after DNA damage. However, despite a remarkable structural and partly functional similarity among p53, p63, and p73, mouse knockout studies revealed an unexpected functional diversity among them. p63 and p73 knockouts exhibit severe developmental abnormalities but no increased cancer susceptibility, whereas this picture is reversed for p53 knockouts. Neither p63 nor p73 is the target of inactivating mutations in human cancers. Genomic organization is more complex in p63 and p73, largely the result of an alternative internal promoter generating NH2-terminally deleted dominant-negative proteins that engage in inhibitory circuits within the family. Deregulated dominant-negative p73 isoforms might play an active oncogenic role in some human cancers. Moreover, COOH-terminal extensions specific for p63 and p73 enable further unique protein-protein interactions with regulatory pathways involved in development, differentiation, proliferation, and damage response. Thus, p53 family proteins take on functions within a wide biological spectrum stretching from development (p63 and p73), DNA damage response via apoptosis and cell cycle arrest (p53, TAp63, and TAp73), chemosensitivity of tumors (p53 and TAp73), and immortalization and oncogenesis (ΔNp73).
Molecular Cloning and Characterization of the von Hippel-Lindau-Like Protein
Authors: Qi Heng , Gervais Michelle L. , Li Wei , DeCaprio James A. , Challis John R.G. , Ohh Michael
Published: May 2022

von Hippel-Lindau (VHL) tumor suppressor protein—inactivated in VHL disease and sporadic kidney cancer—is a component of an E3 ubiquitin ligase complex that selectively ubiquitinates the α subunit of the hypoxia-inducible factor (HIF) transcription factor for subsequent destruction by the 26S proteasome. Here, we report the identification and characterization of the first VHL homologue, VHL-like protein (VLP), located on chromosome 1q21.2. A 676-bp partial cDNA encoding a 139-amino acid protein that is 78% similar to VHL was isolated by reverse transcription-PCR from human brain cerebellum and several cancer cell lines. The expression of VLP transcript is most abundant in the placenta. Like VHL, VLP contains a β domain capable of binding HIFα. However, unlike VHL, it does not contain a recognizable α domain, which is required for nucleating the multiprotein E3 ubiquitin ligase complex. The increased expression of VLP in the presence of VHL attenuated the ubiquitination of HIFα and led to the accumulation of downstream HIF target genes. These results taken together indicate that VLP functions as a dominant-negative VHL to serve as a protector of HIFα.
TAFII70 Isoform-Specific Growth Suppression Correlates With Its Ability to Complex With the GADD45a Protein
Authors: Wang Wei , Nahta Rita , Huper Gudrun , Marks Jeffrey R.
Published: May 2022

TAFII70, a member of the basal transcription complex implicated in p53-mediated transcription, is synthesized as several alternately spliced variants. The predominant forms found in normal and neoplastic breast epithelial cells are shown to be 72 kDa (TAFII70) and 78 kDa (TAFII80). Most cancers express higher levels of the TAFII80 isoform, whereas normal breast epithelia express higher levels of the TAFII70 isoform. Expression of TAFII70, but not TAFII80, causes dramatic growth suppression of normal and transformed breast epithelial cell lines in a p53-independent manner. Growth suppression correlates with mitotic inhibition resulting from an increased number of cells in G2. Both isoforms induce expression of the G2 arrest associated gene, GADD45a, but a novel protein-protein interaction was observed between TAFII70 (not TAFII80) and GADD45a, suggesting that this interaction is important for the observed growth arrest phenotype induced by the TAFII70 isoform. GADD45a null cells are not subject to TAFII70 inhibition, further supporting the relevance of this interaction.
Thiamine Transporter Gene Expression and Exogenous Thiamine Modulate the Expression of Genes Involved in Drug and Prostaglandin Metabolism in Breast Cancer Cells
Authors: Liu Shuqian , Stromberg Arnold , Tai Hsin-Hsiung , Moscow Jeffrey A.
Published: May 2022

In previous studies, we have shown that RNA levels of the thiamine transporter THTR2 were down-regulated in breast cancer tumors in comparison with normal tissues and that THTR2-mediated increases in thiamine uptake activity contributed to increased apoptosis after exposure to ionizing radiation. To further understand the biological effects of the alteration of THTR2 expression, we conducted a DNA microarray study of gene expression in THTR2-transfected breast cancer cells and found that, in addition to increased expression of THTR2 attributable to the transgene, three other genes were up-regulated >2.5-fold in the transfected cells: cytochrome P450 isoform CYP4B1, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and transcription factor CRIP1. In addition, two genes were confirmed to be down-regulated in THTR2-transfected cells: trefoil factor 1 (TFF1) and Rho-GDP dissociation inhibitor (RGDI). Up-regulation of 15-PGDH and CYP4B1 expression was observed in other breast cancer cell lines transfected with THTR2, and down-regulation was observed after suppression of THTR2 with siRNA vectors. To determine the role of exogenous thiamine in the expression of these genes, we analyzed THTR2-transfected breast cancer cells grown in thiamine-depleted medium by quantitative reverse transcription-PCR and showed that three of these five genes showed evidence of regulation by exogenous thiamine in a manner concordant with the effects of THTR2 overexpression. One of the genes up-regulated by THTR2 transfection was down-regulated by thiamine depletion (CYP4B1), and two genes with decreased expression in THTR2-transfected breast cancer cells were up-regulated by thiamine depletion (TFF1 and RGDI). In summary, these studies show unexpected relationships between thiamine metabolism and genes that may be involved in the oncogenesis of breast and lung cancer.
Frequent HIN-1 Promoter Methylation and Lack of Expression in Multiple Human Tumor Types
Authors: Krop Ian , Player Audrey , Tablante Ana , Taylor-Parker Michele , Lahti-Domenici Jaana , Fukuoka Junya , Batra Surinder K. , Papadopoulos Nickolas , Richards William G. , Sugarbaker David J. , Wright Renee L. , Shim Judy , Stamey Thomas A. , Sellers William R. , Loda Massimo , Meyerson Matthew , Hruban Ralph , Jen Jin , Polyak Kornelia
Published: May 2022

HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.
Inhibin Resistance Is Associated with Aggressive Tumorigenicity of Ovarian Cancer Cells
Authors: Steller Michael D. , Shaw Tanya J. , Vanderhyden Barbara C. , Ethier Jean-François
Published: May 2022

Malignant ovarian epithelial tumors have been shown to have decreased inhibin production relative to activin production compared with normal ovarian surface epithelial (OSE) cells and nonmalignant ovarian tumors. Activin stimulates proliferation of many ovarian cancer cell lines. Inhibin antagonizes the action of activin, and inhibin-deficient mice develop gonadal tumors, suggesting that inhibin may be a tumor suppressor. However, its effects on OSE and ovarian cancer cells are unknown. We hypothesize that activin and inhibin are important regulators of biological activity in ovarian cancers. We found that inhibin A decreased murine OSE proliferation, whereas activin A had no effect. Activin A increased the proliferation of four of eight ovarian cancer cell lines (SKOV3, OCC1, OVCAR3, and A2780-s). Inhibin A decreased the proliferation of SKOV3, A2780-s, and OVCAR3 but had no effect on OCC1, ES-2, HEY, A2780-cp, and OVCA429 cells. When injected into nude mice, the inhibin-resistant cancer cell lines resulted in shorter survival time compared with the inhibin-responsive cells. Further investigations on SKOV3 and OCC1 cells showed that activin A increased invasion through Matrigel. Inhibin A decreased both basal and activin-induced proliferation and invasion of SKOV3 but had no effect on OCC1 cells. Reverse transcription-PCR analyses showed that the SKOV3 and OCC1 cells produced activin, but only SKOV3 produced inhibin. Analysis of the activin/inhibin signaling pathways indicated that Smad anchor for receptor activation was elevated in SKOV3 and OCC1 cells and that an up-regulation of the activin receptor expression may explain the inhibin resistance of OCC1 cells. Our results suggest that activin responsiveness may be gained during transformation of OSE cells and that inhibin resistance may contribute to the aggressive behavior of ovarian cancer cells.
EphA2 Induction of Fibronectin Creates a Permissive Microenvironment for Malignant Cells
Authors: Hu Min , Carles-Kinch Kelly L. , Zelinski Daniel P. , Kinch Michael S.
Published: May 2022

Normal and metastatic cells continuously exchange information with the surrounding tissue environment, and this communication governs many aspects of cell behavior. In particular, the physical placement or adhesions of cells within their environment are increasingly understood to facilitate this communication. Classically, cell-cell and cell-extracellular matrix adhesions have been viewed as separable events that are independently controlled. This simple view is changing, as evidence emerges of coordinated regulation of cellular adhesions. Here, we show that the EphA2 tyrosine kinase, which is overexpressed in many aggressive cancers, regulates a fine balance of cell-cell and cell-extracellular matrix adhesions in epithelial cells. EphA2 selectively inhibits cell-cell adhesions by increasing cell attachment and up-regulating the extracellular matrix protein fibronectin. We also show that fibronectin can contribute to important aspects of malignant character. Antibody-based targeting of EphA2 inhibits malignant cell growth by decreasing fibronectin and thereby inducing apoptotic death. Our findings strengthen a concept that cancer progression is regulated by a bidirectional communication between tumor cells and their surrounding microenvironment.
HER-2/neuOverexpression Increases the Viable Hypoxic Cell Population within Solid Tumors without Causing Changes in Tumor Vascularization
Authors: Dragowska Wieslawa H. , Warburton Corinna , Yapp Donald T.T. , Minchinton Andrew I. , Hu Yanping , Waterhouse Dawn N. , Gelmon Karen , Skov Kirsten , Woo Janet , Masin Dana , Huxham Lynsey A. , Kyle Alastair H. , Bally Marcel B.
Published: May 2022

The effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6HER-2) into SCID-Rag2M mice. LCC6HER-2 tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6Vector). Correspondingly, a 2.7-fold increase in trypan blue–excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6HER-2 versus LCC6Vector tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6HER-2 tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content ≥ 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6HER-2 than in LCC6Vector tumors (16.41 ± 8.1% and 5.96 ± 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser536) nuclear factor-κB p65 were significantly elevated in LCC6HER-2 tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1α protein levels was observed in LCC6HER-2 compared with LCC6Vector tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6HER-2 tumors, no significant differences were found (P > 0.05) between LCC6HER-2 and LCC6Vector vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.
Bad-Dependent Rafts Alteration Is a Consequence of an Early Intracellular Signal Triggered by Interleukin-4 Deprivation
Authors: Fleischer Aarne , Ghadiri Ata , Dessauge Frédéric , Duhamel Marianne , Cayla Xavier , Garcia Alphonse , Rebollo Angelita
Published: May 2022

Many molecules are inducibly localized in lipid rafts, and their alteration inhibits early activation events, supporting a critical role for these domains in signaling. Using confocal microscopy and cellular fractionation, we have shown that the pool of Bad, attached to lipid rafts in proliferating cells, is released when cells undergo apoptosis. Kinetic studies indicate that rafts alteration is a consequence of an intracellular signal triggered by interleukin-4 deprivation. Growth factor deprivation in turn induces PP1α phosphatase activation, responsible for cytoplasmic Bad dephosphorylation as well as caspase-9 and caspase-3 activation. Caspases translocate to rafts and induce their modification followed by translocation of Bad from rafts to mitochondria, which correlates with apoptosis. Taken together, our results suggest that alteration of lipid rafts is an early event in the apoptotic cascade indirectly induced by interleukin-4 deprivation via PP1α activation, dephosphorylation of cytoplasmic Bad, and caspase activation.
Histone Deacetylase Inhibitors Up-Regulate the Expression of Tight Junction Proteins
Authors: Bordin Mauro , D'Atri Fabio , Guillemot Laurent , Citi Sandra
Published: May 2022

Histone deacetylase (HDAC) inhibitors promote cell maturation, differentiation, and apoptosis through changes in gene expression. Differentiated epithelial cells are characterized by apical tight junctions (TJ), which play a role in cell-cell adhesion, polarity, and the permeability barrier function of epithelia. The relationship between cellular differentiation and expression of TJ-associated proteins is not known. Here, we investigated whether HDAC inhibitors affect the expression of TJ proteins in cultured cells by immunoblotting, immunofluorescence, and quantitative real-time, reverse transcription-PCR. We find that the HDAC inhibitor sodium butyrate significantly up-regulates the protein levels of cingulin, ZO-1, and ZO-2 in Rat-1 fibroblasts, cingulin in COS-7 cells, and cingulin and occludin in HeLa cells. Levels of mRNA for cingulin, ZO-1, and ZO-2 are also increased in sodium butyrate–treated Rat-1 fibroblasts. Up-regulation of cingulin is reversible and dose dependent and requires de novo protein synthesis and protein kinase activity, because it is inhibited by cycloheximide and by the protein kinase inhibitor H-7. Up-regulation of TJ proteins by sodium butyrate is linked to the ability of sodium butyrate to inhibit HDAC activity, because suberoylanilide hydroxamic acid, a HDAC inhibitor of a different structural class, also up-regulates cingulin, ZO-1, and ZO-2 expression in Rat-1 fibroblasts. These results indicate that cellular differentiation correlates with kinase-dependent up-regulation of the expression of specific TJ proteins.
Fenretinide Reduces Intestinal Mucin-2-Positive Goblet Cells in Chronic Alcohol Abuse
Authors: Melis Marta , Tang Xiao-Han , Mai Karen , Gudas Lorraine J. , Trasino Steven E.
Published: May 2022

Introduction: Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (MUC2) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg/kg/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD. Methods: In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including MUC2 using a 25-day Lieber-DeCarli model of chronic alcohol intake. Results: Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of MUC2 in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands Dll1 and Dll4, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of KLF4, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg/kg/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal Muc2, colonic Muc2, Muc5ac and Muc6 mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand Dll1, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg/kg/day had no effects on any of the goblet cell-related endpoints. Conclusion: These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD.
Pulmonary Resilience: Moderating the Association between Oxygen Exposure and Pulmonary Outcomes in Extremely Preterm Newborns
Authors: Jhaveri Sanghvi Urvi , Wright Clyde J. , Hernandez Teri L.
Published: May 2022

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy associated with high morbidity and mortality. Although most prevalent following extremely preterm birth, BPD is diagnosed at 36 weeks post-menstrual age, when the disease trajectory is underway, and long-term physiological implications may be irreversible. There is an urgent and unmet need to identify how early exposures can be modified to decrease the risk of developing BPD before disease progression becomes irreversible. Extremely preterm newborns encounter a paradox at birth: oxygen is a life-sustaining component of ex utero life yet is undeniably toxic. Attempts at minimizing supplemental oxygen exposure by targeting lower oxygen saturations appear to decrease BPD but may increase mortality. Given the potential association between lower oxygen saturations and increased mortality, practice guidelines favor targeting higher saturations. This uniformly increases oxygen exposure, prompting a cascade of pathogenic mechanisms implicated in BPD development. In this review, we introduce the concept of pulmonary resilience: a homeostatic process driven by the autonomic nervous system (ANS) as a moderator of physiologic stress that when functional, could inform successful environmental adaptation following extremely preterm birth. We hypothesize that infants with early-life ANS dysfunction require a higher oxygen dose for survival; conversely, oxygen exposure could be safely limited in infants with more robust early-life ANS function, an indicator of pulmonary resilience. Characterizing the pulmonary resilience continuum to guide individualized supplemental oxygen dosing may reduce morbidity and mortality in this growing population of extremely preterm infants at risk for BPD.
A Sensitivity Meta-Analysis of Disease-Specific Death in Localized Cutaneous Squamous Cell Carcinoma
Authors: Dessinioti Clio , Platsidaki Eftychia , Stratigos Alexander J.
Published: May 2022

Background: Patients with localized cutaneous squamous cell carcinoma (cSCC) have different risk for disease-specific death (DSD) from patients with metastatic cSCC. Patients and Methods: We conducted a sensitivity meta-analysis to identify the risk factors associated with DSD, in patients with localized cSCC at initial diagnosis (without locoregional or distant metastasis). Results: Nine studies, with 5,205 patients, were included. Median follow-up ranged from 18 to 81 months. The number of deaths due to cSCC ranged from 3 to 40. Patients with immunosuppression were almost 2 times more likely to die from cSCC compared to immunocompetent patients (risk ratio: 1.85, 95% CI: 1.32–2.61). There was a positive but nonsignificant overall association with DSD for depth beyond fat, tumor diameter, presence of perineural invasion, location, and thickness. These results should be interpreted with caution, as there was limited evidence-based data on DSD in localized cSCC, due to the small number of studies reporting DSD, the absence of reporting the margin status, the variability of selected risk factors across studies, and the variability of definition of risk factors. Conclusions: In our meta-analysis, in localized cSCC at initial diagnosis, patients with immunosuppression were at significantly higher risk to die from cSCC. Our findings further highlight the need for a standardized set of risk factors to be included in studies on prognosis of cSCC and for including margin status and DSD among the studied outcomes.
A Case of Traumatic Medial Longitudinal Fasciculus Syndrome Whose Causal Lesion Was Detected by Thin-Section MRI with Susceptibility-Weighted Imaging
Authors: Ueno Yosuke , Honda Shigeru
Published: May 2022

The aim of the study was to report a case of traumatic medial longitudinal fasciculus (MLF) syndrome diagnosed with brain magnetic resonance imaging (MRI) after a head injury. A 71-year-old male complained of diplopia after he was bruised the back of his head when he was hit by a bicycle and fell down. He showed failure of adduction in the right eye, and mild nystagmus was found in the left eye when looking to the left. Convergence was intact. A low-intensity area was found at the middle right site in the lower part of the midbrain using thin-section MRI with susceptibility-weighted imaging (SWI), which suggested a hemorrhage. From the present history, characteristic abnormality of eye movement, and MRI imaging, he was diagnosed with traumatic MLF syndrome. His symptom was resolved, and the eye movement was improved in 2 weeks. A hemorrhage that occurs in the brainstem may be a cause of traumatic MLF syndrome which could be detected by thin-slice MRI with SWI.
Cinema e Corpo
Authors: Saura Soraia Chung ,   Universidade de São Paulo. Escola de Educação Física e Esporte, Zimmermann Ana Cristina ,   Universidade de São Paulo. Escola de Educação Física e Esporte
Published: May 2022

Este volume 9 da Coleção CINUSP trata da relação entre cinema e corpo nos vários campos do conhecimento e é um dos frutos de um ideal de universidade calcado no encontro de saberes. A proposta de duas professoras da Escola de Educação Física e Esporte da Universidade de São Paulo ao CINUSP foi o ponto de partida para a criação de filmes, exibições com debates mensais sobre cinema e corpo. O cinema expressou e produziu ideologias, experimentos e fábulas para o intercâmbio entre o público da educação física e pesquisadores de psicanálise, cinema, música, televisão etc., além de recuperar o entretenimento como espaço de sociabilidade e de encontro com o outro. A liberdade conferida aos pesquisadores e professores na seleção dos filmes possibilitou a emergência de amplo espectro de acontecimentos sociais e poéticos passíveis de debate quando o corpo está em questão. Ressalta-se que as organizadoras elegeram o corpo como objeto da mostra e não as atividades de uma educação física.
Screening of
ABCG5
and
ABCG8
Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program
Authors: Tada Mauricio Teruo , Rocha Viviane Zorzanelli , Lima Isabella Ramos , Oliveira Théo Gremen Mimary , Chacra Ana Paula , Miname Marcio Hiroshi , Nunes Valéria Sutti , Nakandakare Edna Regina , Costa Gurgel Castelo Maria Helane , Jannes Cinthia Elim , Santos Raul D. , Krieger José Eduardo , Pereira Alexandre Costa
Published: May 2022

Background:

Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in
ABCG5/ABCG8
. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program.

Methods:

From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the
ABCG5/8
genes. Clinical and laboratory characteristics of affected individuals were determined.

Results:

Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for
ABCG5/ABCG8
genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean β-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122–521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities.

Conclusions:

Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
Genetic Basis of Left Ventricular Noncompaction
Authors: Rojanasopondist Pakdee , Nesheiwat Leigh , Piombo Sebastian , Porter George A. , Ren Mindong , Phoon Colin K.L.
Published: May 2022

Background:

Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated.

Methods:

Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC.

Results:

We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy.

Conclusions:

LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.
Abstract 16: Addressing Gaps In Cholesterol Management In Primary Cardiovascular Prevention In A Resident Run Internal Medicine Clinic: A Mixed Method Approach
Authors: Acharya Sameer , Senner Jillian , Lee Janette , Berlin Michael , Hanford Holly , Maul Andrew , Pokharel Yashashwi
Published: May 2022

Background:
Provider and system level barriers can delay timely initiation of statin therapy in primary atherosclerotic cardiovascular disease (ASCVD) prevention. A simple, pragmatic and scalable quality improvement (QI) approach is needed to address these gaps.

Methods:
We describe methods and preliminary results of a QI initiative in a resident run internal medicine clinic in Cayuga Medical Center (total 19 residents, 5 attendings, ~200 patients seen/month with 10% no shows). First, we assessed rates of lipids tested and statin use in 40-75 years old patients without ASCVD. Second, we performed a focus group discussion (FGD) among residents, attendings and clinic leadership to understand barriers for statin use. Third, we outlined key actionable items informed by FGD. Finally, we will assess the impact of the intervention.

Findings:
We report baseline data in 325 consecutive patients (Table). Mean age was 55.2 years (50.2% women), 50.6% did not have lipids checked and only 17.5% were on statin therapy in the preceding 3 years. Three major themes from FGD were: lack of automated ASCVD score reporting in electronic medical record (EMR), insufficient clinic time and follow up visits. Subsequently, we adopted automated ASCVD risk reporting in EMR and telemedicine follow up to address identified gaps and associated downstream impact, which is currently ongoing.

Conclusion:
Using mixed-method approach, we describe an implementation strategy to address gaps in cholesterol management in primary prevention patients in a resident run clinic. If effective, this strategy can be a model for other clinics.
Abstract 167: Effects Of Cardiac Rehabilitation After Discharge On Frailty And Balance In Elderly Patients With Cardiovascular Disease
Authors: Hirashiki Akihiro , Nomoto Kenichiro , Kokubo Manabu , Shimizu Atsuya
Published: May 2022

Background:
Cardiac rehabilitation (CR) improves patients’ overall health. However, the benefits of CR after discharge in elderly patients with cardiovascular disease (CVD) are unknown. We therefore compared cardiac function, exercise capacity, and balance between elderly patients who received CR and those who received the current standard of clinical care.

Methods:
In this retrospective study, elderly patients (n=185; mean age, 79.8 years) admitted due to worsening CVD were divided into two groups: those who underwent CR comprising aerobic exercise and resistance training once weekly for 4 months (group C, n=85) and those who received standard clinical care (group U, n=100). All patients underwent cardiopulmonary exercise testing, Kihon Checklist (KCL) frailty assessment, walking speed and timed up-and-go (TUG) measurement, and the Short Physical Performance Battery (SPPB) at discharge and 4 months afterward.

Results:
In group C, the anaerobic threshold (AT) increased from 10.0±1.8 mL/min/kg at baseline to 10.5±2.1 mL/min/kg at 4 months (p=0.032). Comfortable walking speed, TUG, and SPPB at 4 months were improved in group C (p<0.05), but TUG and SPPB did not differ between discharge and 4 months in group U. After adjustment for age, gender, and baseline data, KCL score tended to be improved (p=0.089) and AT, walking speed, TUG, and SPPB were significantly improved in group C (p<0.05).

Conclusions:
CR after discharge is beneficial for elderly patients with CVD. Rather than further increasing cardiac function, CR after discharge decreased frailty and increased exercise capacity, ease of movement, and balance. CR after discharge should be recommended more often for elderly patients with CVD.
Abstract 188: Ischemic Heart Disease Burden On Clinical Outcomes After Percutaneous Left Atrial Appendage Closure In Patients With Atrial Fibrillation In The United States
Authors: Abumoawad Abdelrhman , Wahood Waseem , Barssoum Kirolos , Nagy Ahmed , Lopez-Candales Angel
Published: May 2022

Background:
Percutaneous left atrial appendage closure (PLAAC) is an alternative to anticoagulants for atrial fibrillation patients with elevated stroke risk and contraindication to anticoagulation. We examined the burden of IHD on clinical outcomes after PLAAC.

Methods:
We identified patients from the Nationwide Readmission Database who underwent PLAAC with a Watchman device between 2014-2018 using ICD-9 and 10 codes. Patients were classified into 2 groups based on the presence of IHD. Outcomes were all-cause and cause-specific 30-day readmissions and mortality rate during readmission. Multivariable regression was conducted for 30 days readmission adjusting for patient demographics,hospital characteristics, and Elixhauser Comorbidity Index.

Results:
A total of 18,348 Watchman recipients were identified, of which 8,504 had IHD while 9,844 had no ischemic heart disease (NIHD). Length of stay and cost were not different between groups. However, significant differences were noted in terms of the number of frequent index admission complications between the IHD vs. NIHD group, including transient ischemic attack/Stroke (3.5% Vs. 1.6%, P<0.0001) (Table 1). Although the 30 days readmission rate was higher in the IHD group (7.5% Vs. 6%, P=0.003), there was no difference in mortality. Most frequent causes of readmissions for IHD Vs. NIHD were Acute Kidney Injury (AKI) (26% Vs. 17.3%, P=0.009) and acute heart failure (HF) (24.1% Vs. 17%, P=0.015) (Table 1). In multivariate analysis, ICM PLAAC recipients had higher odds of 30-day readmission compared to NICM (OR=3.7, P=0.4). Renal failure patients have higher odds of 30-day readmission compared to non-renal failure ( OR=1.4, P=0.001).

Conclusion:
Thirty-day readmission rate in patients who underwent PLAAC was higher in the IHD group. However, no difference was noted in mortality between both groups. AKI and acute HF were significant causes of readmission in patients with IHD who underwent PLAAC. Further studies exploring these differences may help to prevent these readmissions.
Abstract 201: Weekend Effect On Pulmonary Embolism: Real World Data
Authors: Abumoawad Abdelrhman , Mark Justin , Mirza Jacqueline , Barssoum Kirolos , Khalife Wissam
Published: May 2022

Background:
Pulmonary embolism (PE) is associated with high morbidity and mortality, there is paucity of data regarding the outcomes of patients with acute high-risk PE presenting on weekends, weekend Effect stems from reductions in staff availability, lack of highly trained endovascular subspecialists to conduct timely therapeutic procedures or inadequate intensive care facilities.

Methods:
We queried the Nationwide Readmissions Database (2016-2019) using ICD-10 codes for patients presenting with acute PE as primary diagnosis, we classified the patients into 2 groups based on whether patients were admitted on weekends or weekdays. We performed a subgroup analysis of patients presenting with high risk PE (shock or cardiac arrest) during the index admission. Outcomes were in-hospital death, stroke (composite of ischemic, hemorrhagic strokes &TIA), intracranial bleed (IC), gastrointestinal (GI) bleed, and 90-day readmission rates.

Results:
167,522, and 55352 patients were admitted on weekends and weekdays, in hospital-mortality was higher for patients presenting on weekends (3.2% vs 2.9%, p<0.0001). Length of stay and total charges were similar between both groups. Weekends’ group had higher readmission rate within 90 days (14.0 vs. 13.6%, p=0.03). Causes of readmissions were also similar (table1). 5,889 and 17,532 patients were admitted on weekends and weekdays with high-risk PE (shock or cardiac arrest). In-hospital mortality rate was not different between groups 45.2% vs. 44.0%, P=0.4, respectively.

Conclusion:
PE patients admitted on weekends have higher mortality rates compared to patients admitted on weekdays. Of those surviving index admissions, weekend patients were also more likely to be readmitted at 90 days. Strategies to mitigate this Weekend Effect should be further explored to reduce mortality and complications.
Abstract 202: Impact Of Productivity Targets And Performance Reviews For Specialty Practices In The Veterans Health Administration
Authors: Kalwani Neil M , Heidenreich Paul A
Published: May 2022

Introduction:
In 2013, the Veterans Health Administration (VHA) introduced a program setting minimum physician productivity targets for specialty practices based on the ratio of total work Relative Value Units to clinical full-time equivalents. Practices with productivity below their targets were required to undergo annual reviews and submit remediation plans. We have previously demonstrated that reviewed cardiology practices experienced large increases in productivity though the contribution from regression toward the mean is unknown.

Hypothesis:
We hypothesized that the introduction of the VHA’s program was associated with larger increases in productivity at low-productivity practices.

Methods:
We extracted productivity metrics from fiscal year 2009-2019 reports for VHA practices in 4 specialties: cardiology, gastroenterology, neurology, and surgery. We identified low-productivity practices using VHA minimum productivity targets. We used linear regression to compare changes in productivity at these practices before and after implementation of the VHA’s program, controlling for specialty and facility level effects.

Results:
Of 4,249 specialty practice-years, we identified 383 as low productivity. Prior to implementation of the VHA’s program, there was evidence of regression toward the mean with relative increases in productivity ranging from 21% for surgery to 27% for cardiology the year after a practice was designated as low productivity. After implementation of the VHA’s program, there was evidence of an independent program effect with an additional relative annual productivity increase of 3.0% (95% CI 1.1 to 4.9%) at these practices. There was no evidence of effect modification for cardiology practices.

Conclusions:
A majority of the increase in productivity observed at low-productivity VHA specialty practices appears to be due to regression toward the mean, with a smaller but significant contribution from the VHA’s productivity program. Policies incentivizing productivity of specialist physicians at the group level may be an effective way to increase care efficiency in integrated healthcare systems. Evaluations of programs targeting low-performing practices should be designed to account for regression toward the mean.
Abstract 203: Inter-rater Reliability Of Myocardial Strain Measurements In Comparison With Ejection Fraction In A Rural, Clinical Setting Using Speckle Tracking Echocardiography
Authors: Brabham David , Muniz Alexandra
Published: May 2022

Global longitudinal strain (GLS) analysis via speckle tracking echocardiography is a relatively new and promising imaging technology for the assessment of structural and functional abnormalities in the heart. GLS can be used in conjunction with left ventricular ejection fraction (LVEF) as a valuable predictor of left ventricular function. In fact, current data suggest strain to be a more effective indicator for ventricular dysfunction than LVEF. Despite its promise, the use of speckle tracking echocardiography has been limited to robust academic and research institutions due to concerns of reliability in clinical settings. Therefore, the hypothesis of this study is that high inter-rater reliability can be obtained in the measurement of mean global longitudinal strain in a non-academic, rural setting. GLS and LVEF were evaluated on twenty-one patients undergoing chemotherapeutic treatment during routine standard-of-care visits. The echocardiograms were performed on each patient by two separate technologists on the same day and the measurements were compared via intra-class correlation coefficient (ICC) values. Briefly, higher inter-rater reliability was observed in GLS (ICC 0.895) compared to LVEF (ICC 0.569), suggesting GLS is a reliable and reproducible measure of systolic function.
Abstract 214: Non-Health Professional Interventions For Hypertension: Systematic Review Comparing Interventions Leveraged In Developed And Developing Economies
Authors: Bushweller Leila , Bhayani Vishwa , Wilson Gwen , Patil Sonal
Published: May 2022

Background:
Non-health professionals, most often in the form of community health workers, have been deployed in both developed and developing economies to improve hypertension outcomes. Variation between developed and developing economies in the type and outcome of these interventions is unknown.

Aim:
Compare the deployment and efficacy of non-health professional interventions targeting hypertension in developed and developing economies.

Methods:
Several databases including Medline were systematically searched until December 2020. All study designs with non-health professional interventions for hypertension were included. Eligible articles were coded by two independent reviewers.

Results:
Of the 23 articles eligible for inclusion, 15 studies (65%) were from developed economies and 8 (35%) from developing economies.

Non-health professional recruitment, selection and intervention durations were similar in developed and developing economies. Positive hypertension and health service utilization outcomes were seen in most studies.

Interventions in developed economies:
Only 33% (5 of 15) of the studies included some form of home visits, while 60% (9 of 15) of interventions focused on group education. Phone calls were incorporated into 47% (7 of 15) of the studies to further promote medication adherence, appointment keeping, or to discuss progress.

Interventions in developing economies:
Home visits were part of 75% (6 of 8) of the studies and only 25% (2 of 8) focused on group education. A single study of the 8 (13%) included phone calls for appointment reminders and was the sole study that was clinic, not community based, and did not report positive outcomes. One study also included one-way outgoing text messages to promote lifestyle changes and medication adherence.

Conclusions:
Developed and developing economies diverge in the type of non-health professional intervention employed. Studies from developed economies mainly include group education with phone calls for individualization, whereas studies in developing economies prioritized home visits. Most studies resulted in positive outcomes suggesting that various forms of non-health professional support are effective for improving hypertension outcomes in diverse settings.