bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Body Composition, Relative Dose Intensity, and Adverse Events among Patients with Colon Cancer
Authors: Cheng En , Caan Bette J. , Cawthon Peggy M. , Evans William J. , Hellerstein Marc K. , Shankaran Mahalakshmi , Nyangau Edna , Campbell Kristin L. , Lee Catherine , Binder Alexandra M. , Meyerhardt Jeffrey A. , Schmitz Kathryn H. , Cespedes Feliciano Elizabeth M.
Published: October 2023

AbstractBackground:
Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178 patients with colon cancer, we assessed muscle and adipose tissue with multiple techniques and examined their associations with relative dose intensity (RDI) and adverse events.
Methods:
We estimated (i) cross-sectional skeletal muscle area (SMA) and total adipose tissue (TAT) area at L3 from computed tomography (CT); (ii) appendicular lean mass (ALM) and total body fat (TBF) mass from dual-energy X-ray absorptiometry (DXA); and (iii) total body skeletal muscle mass using D3-creatine (D3Cr) dilution. We standardized each measurement by its sex-specific standard deviation (SD). The primary outcome was reduced RDI (RDI <85%). The secondary outcome was the number of moderate and severe adverse events during each cycle of chemotherapy. We estimated the associations of muscle and adipose tissue measurements (per SD increase) with reduced RDI using logistic regression and adverse events using generalized estimating equations for repeated measures.
Results:
Higher CT SMA and DXA ALM were significantly associated with a lower risk of reduced RDI [odds ratios: 0.56 (0.38–0.81) for CT SMA; 0.56 (0.37–0.84) for DXA ALM]. No measurements of muscle or adipose tissue were associated with adverse events.
Conclusions:
More muscle was associated with improved chemotherapy completion among patients with colon cancer, whereas muscle and adipose tissue were not associated with adverse events.
Impact:
Considering body composition may help personalize dosing for colon cancer chemotherapy by identifying patients at risk for poor chemotherapy outcomes.
Data from Risk of Colorectal Cancer and Colorectal Cancer Mortality Beginning One Year after a Negative Fecal Occult Blood Test, among Screen-Eligible 76- to 85-Year-Olds
Authors: Dalmat Ronit R. , Ziebell Rebecca A. , Kamineni Aruna , Phipps Amanda I. , Weiss Noel S. , Breslau Erica S. , Burnett-Hartman Andrea N. , Corley Douglas A. , Doria-Rose V. Paul , Green Beverly B. , Halm Ethan A. , Levin Theodore R. , Schottinger Joanne E. , Chubak Jessica
Published: October 2023

AbstractBackground:
Colorectal cancer screening is universally recommended for adults ages 45 to 75 years. Noninvasive fecal occult blood tests are effective screening tests recommended by guidelines. However, empirical evidence to inform older adults’ decisions about whether to continue screening is sparse, especially for individuals with prior screening.
Methods:
This study used a retrospective cohort of older adults at three Kaiser Permanente integrated healthcare systems (Northern California, Southern California, Washington) and Parkland Health. Beginning 1 year following a negative stool-based screening test, cumulative risks of colorectal cancer incidence, colorectal cancer mortality (accounting for deaths from other causes), and non-colorectal cancer mortality were estimated.
Results:
Cumulative incidence of colorectal cancer in screen-eligible adults ages 76 to 85 with a negative fecal occult blood test 1 year ago (N = 118,269) was 0.23% [95% confidence interval (CI), 0.20%–0.26%] after 2 years and 1.21% (95% CI, 1.13%–1.30%) after 8 years. Cumulative colorectal cancer mortality was 0.03% (95% CI, 0.02%–0.04%) after 2 years and 0.33% (95% CI, 0.28%–0.39%) after 8 years. Cumulative risk of death from non-colorectal cancer causes was 4.81% (95% CI, 4.68%–4.96%) after 2 years and 28.40% (95% CI, 27.95%–28.85%) after 8 years.
Conclusions:
Among 76- to 85-year-olds with a recent negative stool-based test, cumulative colorectal cancer incidence and mortality estimates were low, especially within 2 years; death from other causes was over 100 times more likely than death from colorectal cancer.
Impact:
These findings of low absolute colorectal cancer risk, and comparatively higher risk of death from other causes, can inform decision-making regarding whether and when to continue colorectal cancer screening beyond age 75 among screen-eligible adults.
Supplementary Figure S8 from Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer
Authors: Anobile Dario P. , Salaroglio Iris C. , Tabbò Fabrizio , La Vecchia Sofia , Akman Muhlis , Napoli Francesca , Bungaro Maristella , Benso Federica , Aldieri Elisabetta , Bironzo Paolo , Kopecka Joanna , Passiglia Francesco , Righi Luisella , Novello Silvia , Scagliotti Giorgio V. , Riganti Chiara
Published: October 2023

Levels of progesterone, testosterone and respective receptors in non-small cell lung cancer cells
a-b. Levels of progesterone (panel a) and testosterone (panel b), measured by ELISA (technical triplicates), in female (F)-derived NCI-H1385 and NCI-H1975 cells, and in male (M)-derived A549 and NCI-H1650 cells. Data are means+SD (n=3, biological replicates). °p<0.05: M-derived cells versus mean of F-derived cells (ANOVA). c-d. Progesterone receptor (PR; panel c) and androgen receptor (AR; panel d) mRNA, measured by RT-PCR (technical triplicates). The relative expression of each gene in NCI-H1385 cells was considered 1. Data are means + SD (n=3, biological replicates). ***p<0.001: NCI-H1975 cells versus NCI-H1385; °°p<0.01: M-derived cells versus mean of F-derived cells (ANOVA). e. Immunoblot of the indicated proteins in nuclear extracts. TBP is included as control of equal protein loading. The image is representative of one of three experiments.
Supplementary Figure S15 from Autocrine 17-β-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer
Authors: Anobile Dario P. , Salaroglio Iris C. , Tabbò Fabrizio , La Vecchia Sofia , Akman Muhlis , Napoli Francesca , Bungaro Maristella , Benso Federica , Aldieri Elisabetta , Bironzo Paolo , Kopecka Joanna , Passiglia Francesco , Righi Luisella , Novello Silvia , Scagliotti Giorgio V. , Riganti Chiara
Published: October 2023

Letrozole sensitizes xenografts to a second cycle of pembrolizumab by modulating the tumor-associated immune-environment.
60 Hu-CD34+NSG mice bearing female-derived ERα lowNCI-H11385 and ERα highNCI-H1975 tumors, male-derived ERα lowA549 and ERα highNCI-H1650 tumors (15/tumor type) were treated for 5 weeks with pembrolizumab+letrozole with 10 mg/kg i.p. of 100 µL saline solution of pembrolizumab (day 1) followed by 5 mg/kg i.p. (days 7, 14, 21, 28, 35), and 1 mg/kg per os of 100 µL saline solution of letrozole daily (days 1-35), and then divided into three cohorts of 20 animals (n=5 mice/tumor type within each cohort). The first cohort of animals (left panel) was left untreated until week 15 (-Pemb-Letr); the second cohort (middle panel) was treated with 1 mg/kg per os of 100 µL saline solution of letrozole daily until week 15 (+Letr); the third cohort (right panel) was treated with 1 mg/kg per os of 100 µL saline solution of letrozole daily from week 6 to week 10, and then with pembrolizumab+letrozole from week 11 to week 15 (+Pemb+Letr). a. Tumor growth was monitored daily using calipers. Data are presented as mean volumes+ SD. **p<0.01, ***p<0.001: volume of female ERα lowNCI-H1385 and ERα highNCI-H1975 tumors (left panel), or ERα highNCI-H1975 tumors (middle-right panels) versus mean volume of male ERα lowA549 and ERα highNCI-H1650 tumors. b. PD-L1 expression was measured using flow cytometry on dissociated tumor cells after explants at week 15 (n=5/group). *p<0.05: +Pemb+Letr versus -Pemb-Letr (NCI-H1650 tumors), +Letr versus -Pemb-Letr (NCI-H1385 tumors); **p<0.01: +Pemb+Letr versus -Pemb-Letr (NCI-H1385 tumors); ***p<0.001: +Letr/+Pemb+Letr versus -Pemb-Letr (NCI-H1975 tumors) (ANOVA). c-e. On TILs isolated from tumor extracts (week 15), the percentage of CD8+Ki67+IFNγ+cells (panel c), CD56+Ki67+IFNγ+cells (panel d), and Vγ9+Ki67+IFNγ+cells (panel e) was measured by flow cytometry (n=5/group). CD8+Ki67+IFNγ+cells: *p<0.05: +Pemb+Letr versus -Pemb-Letr (NCI-H1975 and NCI-H1650 tumors), ***p<0.001: +Pemb+Letr versus -Pemb-Letr (NCI-H1385 tumors). CD56+Ki67+IFNγ+cells: *p<0.05: +Pemb+Letr versus -Pemb-Letr (NCI-H1385, NCI-H1975 and NCI-H1650 tumors). Vγ9+Ki67+IFNγ+cells: *p<0.05: +Pemb+Letr versus -Pemb-Letr (NCI-H1385, NCI-H1975 and NCI-H1650 tumors) (ANOVA).
Supplementary Figure S3 from Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Adjuvant Therapy Era
Authors: Dermawan Josephine K. , Kelly Ciara , Gao Zhidong , Smith Shaleigh , Jadeja Bhumika , Singer Samuel , Tap William D. , Chi Ping , Antonescu Cristina R.
Published: October 2023

Supplementary Figure 3. Genomic risk groups versus tumor size and mitotic rate.
Supplementary Data 1 from Uncoupling CD4+ TIL-Mediated Tumor Killing from JAK-Signaling in Melanoma
Authors: Draghi Arianna , Presti Mario , Jensen Agnete W.P. , Chamberlain Christopher A. , Albieri Benedetta , Rasmussen Anne-Christine K. , Andersen Mads H. , Crowther Michael D. , Svane Inge Marie , Donia Marco
Published: October 2023

CD4+ TILs from melanoma can exert cytotoxic activity against autologous tumor cells (GFP+TCL#17)
Figure S3 from Intratumoral IL15 Improves Efficacy of Near-Infrared Photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: October 2023

Supplementary Fig. S3. Immunohistochemical evaluation of Ki-67 positive cancer cells in hIL-15-MC38 or parental MC38 tumors.
Supplementary Fig. S8 from Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis
Authors: Pradhan Anjan K. , Modi Jinkal , Maji Santanu , Kumar Amit , Bhoopathi Praveen , Mannangatti Padmanabhan , Guo Chunqing , Afosah Daniel K. , Mochel Mark C. , Mukhopadhyay Nitai D. , Kirkwood John M. , Wang Xiang-Yang , Desai Umesh R. , Sarkar Devanand , Emdad Luni , Das Swadesh K. , Fisher Paul B.
Published: October 2023

Comparative effects of DMSO and IVMT-Rx-3 on Treg populations
Supplementary Fig. S4 from Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis
Authors: Pradhan Anjan K. , Modi Jinkal , Maji Santanu , Kumar Amit , Bhoopathi Praveen , Mannangatti Padmanabhan , Guo Chunqing , Afosah Daniel K. , Mochel Mark C. , Mukhopadhyay Nitai D. , Kirkwood John M. , Wang Xiang-Yang , Desai Umesh R. , Sarkar Devanand , Emdad Luni , Das Swadesh K. , Fisher Paul B.
Published: October 2023

PDZ1i was outperformed by IVMT-Rx-3
Figure S2 from A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer
Authors: Habault Justine , Schneider Jeffrey A. , Ha Susan , Ruoff Rachel , Pereira Luiza D. , Puccini Joseph , Ranieri Michela , Ayasun Ruveyda , Deng Jiehui , Kasper Amanda C. , Bar-Sagi Dafna , Wong Kwok-Kin , Zoubeidi Amina , Claessens Frank , Wise David R. , Logan Susan K. , Kirshenbaum Kent , Garabedian Michael J.
Published: October 2023

Comparison of MPC309 antiproliferative activity in DU145, PC3, LNCaP and 22Rv1 and effects on AR-dependent gene expression
Data from A Carbonic Anhydrase IX/SLC1A5 Axis Regulates Glutamine Metabolism Dependent Ferroptosis in Hypoxic Tumor Cells
Authors: Venkateswaran Geetha , McDonald Paul C. , Chafe Shawn C. , Brown Wells S. , Gerbec Zachary J. , Awrey Shannon J. , Parker Seth J. , Dedhar Shoukat
Published: October 2023

Abstract
The ability of tumor cells to alter their metabolism to support survival and growth presents a challenge to effectively treat cancers. Carbonic anhydrase IX (CAIX) is a hypoxia-induced, metabolic enzyme that plays a crucial role in pH regulation in tumor cells. Recently, through a synthetic lethal screen, we identified CAIX to play an important role in redox homeostasis. In this study, we show that CAIX interacts with the glutamine (Gln) transporter, solute carrier family 1 member 5 (SLC1A5), and coordinately functions to maintain redox homeostasis through the glutathione/glutathione peroxidase 4 (GSH/GPX4) axis. Inhibition of CAIX increases Gln uptake by SLC1A5 and concomitantly increases GSH levels. The combined inhibition of CAIX activity and Gln metabolism or the GSH/GPX4 axis results in an increase in lipid peroxidation and induces ferroptosis, both in vitro and in vivo. Thus, this study demonstrates cotargeting of CAIX and Gln metabolism as a potential strategy to induce ferroptosis in tumor cells.
Supplementary Figure 4 from Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation
Authors: Yagi Taro , Sawada Kenjiro , Miyamoto Mayuko , Shimizu Aasa , Oi Yukako , Toda Aska , Nakamura Koji , Kinose Yasuto , Kodama Michiko , Hashimoto Kae , Kimura Tadashi
Published: October 2023

Supplementary Figure 4 shows that the knockdown of VEGFA significantly inhibited the expression level of miR-143-3p, followed by the upregulation of PAI secretion from OC cells.
Supplementary Figure 1 from LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation
Authors: Zhang Shenghua , Zhang Zheng , Liu Xiaolong , Deng Yibin , Zheng Jian , Deng Jieqiong , Wang Yirong , Guo Binbin , Li Fanrong , Chen Xiaoyue , Pan Yacheng , Wang Jieyu , Lu Jiachun , Wu Siqi , Guo Qiang , Zhou Yifeng
Published: October 2023

Screening of candidate lncRNAs and biologic characterization of LINC00887
Data from Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation
Authors: Yagi Taro , Sawada Kenjiro , Miyamoto Mayuko , Shimizu Aasa , Oi Yukako , Toda Aska , Nakamura Koji , Kinose Yasuto , Kodama Michiko , Hashimoto Kae , Kimura Tadashi
Published: October 2023

Abstract
Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan–Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings.
Implications:
Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.
TABLE 1 from Change in Neighborhood Socioeconomic Status and Adherence to the Cancer Prevention Lifestyle Guidelines in Hispanic/Latino Adults: Results from the HCHS/SOL Study
Authors: Pichardo Margaret S. , Pichardo Catherine M. , Talavera Gregory A. , Gallo Linda C. , Kuo Charlene C. , Castañeda Sheila F. , Chambers Earle C. , Daviglus Martha L. , Pirzada Amber , Perreira Krista M. , Sotres-Alvarez Daniela , Peña Ortiz Tania Yadhira , Plascak Jesse J.
Published: October 2023

Weighted baseline characteristics of U.S. Hispanic/Latino adults, recruited from 2008–2011, N = 11,909
Evaluating a Questionnaire in Telephone Balance Consultations during the Coronavirus Disease 2019 Pandemic
Authors: Kaleva Anna I. , Leach Laura , Fahmy Fahmy , Truman Lucy A , Martinez del Pero Marcos
Published: October 2023

Introduction: During the coronavirus disease 2019, pandemic clinical practice had to change, and this study trialled a diagnostic questionnaire to assess patients with dizziness over the telephone. Methods: All 115 patients awaiting otorhinolaryngological assessment for balance were randomised to receive a dizziness questionnaire in the post prior to their telephone consultation or not. Consultation outcomes were recorded by the clinicians conducting the consultation. Follow-up data were collected in June 2022 for final outcomes. Results: 82/115 patients had consultations with complete data collection: 35 in the questionnaire group (QG) and 47 in the no questionnaire group (NQG), with a 70% response rate in the QG. Clinicians made a diagnosis in 27/35 QG consultations versus 27/47 NQG consultations. Nine out of 35 QG patients required additional investigations compared to 34/47 in the NQG (p < 0.05). Only 6/35 QG patients needed additional telephone follow-up, compared to 20/47 NQG patients (p < 0.05). Conclusion: Using a diagnostic questionnaire increased clinicians’ ability to come to a diagnosis in telephone consultations.
Efficacy and Safety of Cold Snare Polypectomy of Colorectal Polyps 10–15 mm with a Hybrid Snare: A Prospective Observational Pilot Study
Authors: Ulrich Jörg D , Rechberger Paul , Bachmann Jeannine , Herner Alexander , v. Figura Guido , Lahmer Tobias , Phillip Veit , Mayr Ulrich , Haller Bernhard , Jesinghaus Moritz , Schmid Roland M. , Abdelhafez Mohamed , Schlag Christoph
Published: October 2023

Introduction: Cold snare polypectomy (CSP) is a safe and effective procedure for small colorectal polyps ≤9 mm. There are only limited data regarding CSP of larger neoplastic lesions. This study evaluated the efficacy and safety of CSP for polyps between 10 and 15 mm in size. Methods: In this prospective single-arm observational pilot study, patients with a least one polyp 10–15 mm were included. These polyps were preferably removed by CSP using a dedicated hybrid snare. The primary outcome was the histological complete resection rate (CRR) determined by pathologically negative margins of the specimen and no neoplastic tissue obtained from biopsies of the resection site margin. Secondary outcomes were en bloc resection rate, failure of CSP, and incidence of adverse events. Results: A total of 61 neoplastic polyps were removed from 39 patients. Overall CRR was 80.3% (49/61). CSP was feasible in 78.7% (48/61) of polyps and the CRR in this group was 85.4% (41/48). When CSP failed (13/61; 21.3%), lesions were successfully resected by immediate HSP using the same snare with a CRR of 61.5% (8/13) in this group. One patient presented delayed hemorrhage after HSP of a polyp but successful hemostasis was achieved with two hemoclips. No other adverse events occurred. No recurrence was seen on follow-up colonoscopy in cases with incomplete resected polyps. Conclusion: CSP seems to be efficient and safe in removing colorectal polyps up to 15 mm. A hybrid snare seems to be particularly advantageous for these polyps as it allows immediate conversion to HSP if CSP might fail in larger polyps. This trial is registered at ClinicalTrials.gov (NCT04464837).
How to Control Exposure to Fifth-Generation Radiofrequencies in Preterm Newborns in Incubator
Authors: Chardon Karen , Delanaud Stéphane , Tourneux Pierre , Stephan Blanchard Erwan
Published: October 2023

Infant and family centered development care reduces infant distress and supports the parent and infant’s individual abilities. However, a new environmental factor is daily encountered: the radiofrequency electromagnetic fields (RF EMFs) with the most recent fifth-generation (5G) technology. Currently, the effects of RF EMF during development are discussed in animal models. The neonatal intensive care units are not spared from this stressor. The objective of this study was to evaluate the efficacy of a novel, electromagnetically insulating incubator cover to prevent the preterm infant from RF EMF exposure. A personal dosimeter was placed on the mattress of a closed incubator. Periods of exposure to low, medium, and high levels of 5G RF were delivered in the presence or absence of the incubator cover. The use of a silver-copper cover reduced the intensity of 5G radiofrequency levels from 52% to 57% (p < 0.0001), allowing to easily apply the precautionary principle.
Impact of Obesity on Postoperative Complications after Lateral Skull Base Surgery: A Systematic Review
Authors: Bridgham Kelly , Shikara Meryam , Ludeman Emilie , Eisenman David J.
Published: October 2023

Introduction: The relationship between obesity and complications after lateral skull base tumor resection is not clear. There is conflicting evidence regarding the incidence of postoperative complications in this patient population. The purpose of this study is to examine the relationship between obesity and outcomes following lateral skull base tumor resection. Data Sources: Data were extracted from PubMed, Embase, CINAHL, and Cochrane CENTRAL. Methods: Included studies assessed the relationship between obesity and outcomes following lateral skull base tumor removal. Studies with ≤5 patients, pediatric patients, duplicate patient populations, or insufficient data were excluded. Two independent investigators reviewed each study for inclusion. A third reviewer served as a tie-breaker for any conflicts. Extracted data includes patient demographics, tumor pathology, surgical approach, and postoperative outcomes including incidence of cerebrospinal fluid (CSF) leak and other postoperative complications, length of stay (LOS), and readmission and reoperation rates. Descriptive statistics were used to compare postoperative outcomes for obese and nonobese controls. Results: 14 studies met final inclusion criteria. Nine studies evaluated the relationship between obesity and CSF leaks. Four studies found a significant increase in postoperative CSF leak in obese patients compared to nonobese controls. The remaining studies trended toward an increased incidence of CSF leak in the obese population but did not reach statistical significance. One out of seven studies found that obesity increased postoperative LOS, and one out of five studies found that obesity increased reoperation rates following tumor resection. Conclusions: Based on the results, obesity does not appear to increase LOS, readmission, or reoperation rates after lateral skull base tumor resection. The relationship between obesity and postoperative CSF leak, however, warrants further analysis.
The Impact of Cue-Elicited Multisensory Imagery on Alcohol Craving: A Randomised Controlled Trial
Authors: Kiyak Ceyda , Deluca Paolo , Norton Sam , Simonetti Matilde E. , Preti Emanuele
Published: October 2023

Introduction: Elaborated intrusion theory suggests that imagery is central to craving; however, the possibility that cue-elicited multisensory imagery produces such urges has not been studied enough in the literature. Thus, we investigated the role of cue-elicited multisensory imagery on alcohol craving in individuals who are hazardous and social drinkers compared to mental and neutral imagery conditions. Methods: In an online experiment, hazardous and social drinkers (N = 348) between 18 and 45 years old were randomised to multisensory, mental, and neutral imagery exposure. The level of craving intensity was measured before and after imagery exposure. Also, participants rated vividness and sensory features scales after the exposure. Results: The level of craving was significantly higher in multisensory imagery condition compared to neutral condition (b = 1.94, p < 0.001, SE = 0.30, t(344) = 6.52, standardised mean difference [SMD] = 0.89) and in mental imagery condition compared to neutral condition (b = 1.82, SE = 0.30, t(344) = 6.52, p < 0.001, SMD = 0.83). The difference between the level of craving intensity between the multisensory and mental was not significant (b = 0.12, SE = 0.22, t(344) = 0.53, p = 0.594, SMD = 0.06). Moreover, craving intensity in response to multisensory versus neutral imagery was significantly stronger among hazardous drinkers (b = −2.90, SE = 0.83, t(341) = −3.50, p < 0.001). The level of vividness was not significantly different between any conditions. The difference between levels of sensory features was higher in multisensory imagery condition compared to neutral (b = 0.95, SE = 0.30, t(345) = 3.17, p = 0.002, SMD = 0.49) and mental imagery condition (b = 0.67, SE = 0.23, t(345) = 2.36, p = 0.004, SMD = 0.35). Conclusion: Results suggest that cue-elicited multisensory imagery may be a useful tool for eliciting alcohol craving responses and provide an additional means for better understanding the multi-layered mechanism of craving.
Granulocytic Sarcoma Mimicking Cholesteatoma: Beware the Temporal Bone in Haematological Patients
Authors: Mayani-Mayani Karan , González-Arnay Emilio , Acosta-Criado Luis , Abbas-Khoja Nassr-Aldin , Abad-Collazo M. Eugenia , García-Viera Manuel , Raya Sánchez José-Maria , Govantes-Rodríguez José
Published: October 2023

Granulocytic sarcoma is a myeloid neoplasm that can occur in isolation or in association with acute leukaemia. The temporal bone represents a sanctuary site for myeloid progenitors: granulocytic sarcoma may develop in this location before or concomitantly with the onset of acute leukaemia. This atypical presentation with clinical and radiological data that closely mimic those of cholesteatoma often delays an accurate diagnosis. We here describe the clinical case of a 28-year-old male with granulocytic sarcoma of the external auditory canal that preceded the relapse of promyelocytic leukaemia.
Discriminant Analysis Using Gabor Filter Sets for Lobular Endocervical Glandular Hyperplasia: Numerical Interpretation of Nuclear Atypia by Gabor Filter Features
Authors: Kimura Fumikazu , Ohshima Kengo , Shirai Keiichiro , Kanai Ryo , Sonohara Masaki , Ishii Keiko
Published: October 2023

Introduction: Lobular endocervical glandular hyperplasia (LEGH) is a benign lesion; however, it is considered to be the origin of gastric-type adenocarcinoma in the uterine cervix, and early diagnosis is important. At Shinshu University Hospital, screening of LEGH cells is based on the difference in color tone of cytoplasmic mucin on Papanicolaou staining and detection of gastric mucin using HIK1083-labeled latex agglutination assay. However, it is sometimes difficult to distinguish LEGH cells with subtle nuclear atypia from endocervical (EC) cells. Methods: We calculated the Gabor filter features (mean signal value, standard deviation, skewness, kurtosis) from the nuclei of cytological specimens in EC cells (37 cases) and LEGH cells (33 cases) using microscopic images, and we performed statistical analysis and discriminant analysis by linear support vector machine (LSVM) using these features. A Gabor filter is a linear filter defined as a mathematical representation of the mammalian visual system. Gabor filters with three wavelengths and eight angles were used for analysis. Results: Gabor filter features in EC cells were higher than in LEGH cells, demonstrating that the gradient of LEGH cell nuclei was milder than that of EC cell nuclei. The accuracy calculated using all Gabor filters was 91.0% and the accuracy of four Gabor filters (λ = 2/3π and θ = 0°, 45°, 90°, 135°) was 88.9%. High accuracy with low computation costs was achieved by reducing the number of features used for LSVM. Conclusion: The application of a Gabor filter with convolutional processing resulted in the edges of LEGH cells being slightly rough and thick, whereas those of EC cells were fine and thin. Thus, it is thought that the frequency of abrupt gradients of pixels was higher in EC cells than in LEGH cells, and the gradient of chromatin distribution in LEGH cell nuclei was milder than that in EC cell nuclei. It was possible to evaluate nuclear findings of EC and LEGH cells objectively by quantifying morphological features of nuclei using Gabor filters. It was possible to differentiate EC cells from LEGH cells using LSVM using Gabor filter features.
An Assessment of the Physical Fitness of Senior High School Learners: Basis for the Development of a Home-Based Physical Fitness Plan
Authors: Dominado Noel L.
Published: October 2023

This study was conducted to determine the Physical Fitness Levels of Learners during the Lockdown Period: Basis for the Development of a Home-Based Physical Fitness Plan: To achieve the purpose of the study, the descriptive research design was used. Seventy-six (76) eleventh graders Health Optimizing Physical Education Accountancy, Business Management learners of Senior High School in Magalang Stand Alone 2 in the School Year 2020-2021 served as respondents of the study. The result revealed that body mass index marked a case of overweight and underweight, the respondents’ health-related fitness show above normal, needs improvement cardiovascular endurance, fair and needs improvement muscular strength. However, some are fair and need improvement in hamstring flexibility, and needs improvement in left shoulder girdle flexibility. Furthermore, the skill-related fitness of the respondents shows poor, fair, and needs improvement agility. Furthermore, poor and needs improvement balance, fair and needs improvement coordination. However, needs improvement and developing performance speed. Lastly, needs improvement in the leg, while needs improvement in reaction time. It is suggested the development of effective preventive strategies for all unfit students who are at high risk of being underweight and overweight and the design of programs that will enhance the fitness of students’ health and skill-related fitness.
Abstract 100: Multi-omics And Single Nucleus Transcriptomics Reveal Aberrant Adaptive Immune Responses In Human Bicuspid Aortic Valves
Authors: Blaser Mark C , Reichart Daniel , Sonawane Abhijeet , Schlotter Florian , Halu Arda , Passos Livia Silva A , DeLaughter Daniel , Zhou Wunan , Blankstein Ron , DI CARLI MARCELO , Nunes Maria D , Billaud Marie , Sabe Ashraf A , Robson Simon , Body Simon C , Muehlschlegel Jochen D , Seidman Jonathan G , Seidman Christine E , Aikawa Masanori , Singh Sasha A , Aikawa Elena
Published: October 2023

Introduction:
Bicuspid aortic valve (BAV) is the most common cause of adult congenital heart disease. Patients with BAVs comprise <2% of the population but represent ~50% of valve replacement surgeries and the pathogenic mechanisms underlying this disproportionate incidence of calcific aortic valve disease (CAVD) are unknown. We aimed to identify molecular contributors to accelerated disease in BAV-CAVD.

Methods:
Bulk multi-omics (miRNA-seq, RNA-seq, proteomics) was performed on 70 human aortic valves (11 non-diseased; fibrotic and calcific portions of 32 tricuspid aortic valves [TAVs] and 27 BAVs with CAVD). Single nuclei RNA-seq (snRNA-seq) was completed on 54,608 nuclei from 13 additional human valves (4 non-diseased; 5 TAVs and 4 BAVs with CAVD).

Results:
Calcific burden did not differ between diseased TAVs and BAVs (p=0.77), but BAV mineralization was significantly accelerated by 11.5±1.7 years vs. TAVs (p<0.001). Latent factor-based integration of covariate-corrected multi-omics analyses (q<0.05), CT-derived valve calcification, and 29 clinical parameters uncovered extensive involvement of adaptive immune responses where T cell/B cell inflammatory activation associated with autoimmune signals was enhanced in the early stages of BAV disease. Integrated multi-omics also revealed significantly elevated platelet activation potentially as a result of lifelong exposure to the high-shear BAV microenvironment, and implicated altered SLIT-ROBO signaling in BAV-CAVD progression. snRNA-seq identified 5 major cell types (27 states) in human aortic valves: valvular interstitial cells (65% of cells; 7 states), endothelial cells (10%; 4 states), macrophages (13%, 7 states), T cells (8%; 5 states), and B cells (3%; 4 states). CAVD drove differentiation of valve interstitial cells along distinct myofibrogenic (
ACTA2/CARMN/MYH11
-high) vs. osteogenic (
RUNX2/CDH11/POSTN
-high) lineages, induction of endothelial-to-mesenchymal transition in valve endothelium and significant accumulation of specific macrophage and T-cell states (p<0.05) in BAV-CAVD.

Conclusions:
Aberrant adaptive immune responses are critical drivers of BAV-CAVD, and our findings delineate a novel strategy for discovery of morphology-specific therapeutics.
Abstract 104: Gene Regulation By RNA Granule Formation In Atherosclerosis
Authors: Wang Kristin M. , De Jong Annika , Cyr Yannick , Newman Alexandra , van Solingen Coen , Moore Kathryn J
Published: October 2023

Background:
Atherosclerosis, the leading cause of cardiovascular disease related death, is a chronic inflammatory condition incited by the accumulation of low-density lipoproteins (LDL) and recruitment of macrophages and smooth muscle cells (SMCs) in the arterial intima. Both macrophages and SMCs become lipid laden foam cells that persist in the arterial vasculature, inciting chronic inflammation and plaque formation. A better understanding of the mechanisms underlying this maladaptive inflammatory response may reveal novel therapeutic strategies for intervention.

Hypothesis:
We hypothesize that the transformation into a foam cell state, a process that requires transcriptional rewiring, is facilitated by stress granules (SGs). SGs are cytoplasmic membrane-less organelles that sequester translation initiation factors, mRNAs, and noncoding RNAs as a result of stress. We previously reported that SG formation is increased in macrophages and vascular smooth muscle cells (SMCs) in plaques of atherosclerotic mice, and can be induced in vitro during cellular cholesterol loading. However, the consequences of SG formation and the transcripts sequestered by these organelles remain unknown

Methods and Results:
A current limitation in studying SG biology is the lack of in vivo models to track and isolate these dynamic structures. Using CRISPR-Cas9, we generated mice with a 3x-HA-tag on the SG marker G3BP1 in C57BL6 mice, allowing us to identify and purify SGs in vivo and in isolated primary cells. In HA-tagged G3BP1 mice fed western diet, we observe staining for HA-G3BP1 in macrophages and smooth muscle cells localized to the necrotic core and fibrous cap of atherosclerotic plaque. Furthermore, qRT-PCR on lipid laden cells revealed changes in known stress granule markers and transcripts involved in immune regulation.

Conclusion:
Our data support a role for SGs in repressing the translation of RNA transcripts in lipid-laden foam cells that accumulate in atherosclerotic plaque. Further study of the specific proteins and RNA transcripts sequestered in SGs of foam cells may reveal how they alter gene expression to facilitate cellular phenotypic changes in the plaque.
Abstract 115: Angptl3 Deficiency Impairs Triglyceride-rich Lipoprotein Production and Produces Adaptive Changes in Hepatic Lipid Metabolism
Authors: Burks Kendall H , Xie Yan , Gildea Michael , Neufeld Thomas , Alisio Arturo , Fisher Edward , Davidson Nicholas , Stitziel Nathan O
Published: October 2023

Rationale:
Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates lipolytic pathways in the metabolism of circulating lipoproteins, its potential hepatocyte-specific role in very low-density lipoprotein (VLDL) assembly and secretion remains unknown.

Methods:
We established hepatocyte cell culture systems, including CRISPR/Cas9-edited ANGPTL3 “knock out” (KO) HepG2 cells and isogenic wild type controls. Radiolabeling was used to quantify apolipoprotein and triglyceride synthesis and secretion. LDL receptor (LDLR) expression and function were determined using western blot, flow cytometry, and confocal microscopy. Bulk RNA sequencing was used to compare global transcript-level changes between wild type and KO cells. Intracellular neutral lipid species were quantified by mass spectrometry-based targeted lipidomics.

Results:
We observed a statistically significant reduction of approximately 50% in apolipoprotein B100 (apoB100) secretion in ANGPTL3 KO HepG2 cells relative to wild type. We also observed statistically significant reductions ranging from 30-50% in the secretion of radiolabeled triglycerides from KO cells. Furthermore, KO cells showed increased LDLR expression and uptake of BODIPY-labeled LDL compared to wild type HepG2 cells. RNA sequencing demonstrated significantly altered expression of key genes within GO terms related to lipid metabolic processes and associated subcellular compartments. Targeted lipidomic analysis showed KO cells exhibited significant reductions in seven of 47 triglyceride species analyzed; overall, neutral lipid accumulation was not observed in KO cells.

Conclusions:
Our results point to an important intrahepatic role for ANGPTL3, suggesting ANGPTL3 deficiency leads to the production of fewer lipoprotein particles and corresponding adaptive changes in hepatic lipid metabolism.
Abstract 117: Structure Function Analysis Of Guinea Pig And Human Apolipoprotein E To Obtain Insight Into Their Role In Cardiovascular Disease
Authors: Celis George , Nguyen Jasmine , Narayanaswami Vasanthy
Published: October 2023

Apolipoprotein (apo) E3 (299 amino acids) is a major cholesterol transport protein in the plasma and brain of humans, with the isoform apoE4 considered a risk factor for cardiovascular and Alzheimer’s diseases (CVD and AD). The molecular basis underlying the link between apoE4, and CVD/AD is poorly understood. Previous studies have identified the C-terminal domain (CTD) in promoting protein-lipid, protein-protein and protein-amyloid peptide interactions. In the current study, apoE from
Cavia porcellu
s (guinea pig, GP) was used as a non-transgenic model to further understand the role of apoE4, since it lacks residues 193-197 and 246-252 of apoE4. We hypothesize that apoE4 CTD plays a critical role in lipid binding, protein folding and amyloid peptide interaction. Recombinant wildtype (WT) GP apoE and insertion mutants GP apoE/Ins193- 197/Ins246-252, and apoE4, and the corresponding deletion mutants apoE4/D193-197/D246-252 were generated. Western blot with anti-apoE4 antibody revealed cross reactivity with GP apoE. Circular dichroism spectroscopy of the variants revealed troughs at 208 and 222 nm indicting that they retained the helical structure observed in WT apoE4. WT GP apoE solubilizes lipids more efficiently than apoE4. Similarly, apoE4/D193-197/D246-252 displayed increased, while GP apoE/Ins193- 197/Ins246-252 showed decreased lipid solubilization ability compared to their WT counterparts. Limited proteolysis analysis indicates that GP apoE was the least susceptible to degradation by trypsin compared to apoE3 and apoE4. Fluorescence analysis using the extrinsic fluorophore anilinonaphthalene sulfonic acid suggests that GP apoE possesses a greater protein surface hydrophobicity than apoE3 and apoE4. Future studies will assess the ability of these variants to promote cholesterol efflux and Aβ binding to gain a better understanding of the role apoE4 in CVD and AD.
Abstract 127: A Targeted Nanofiber Loaded With Liver X Receptor Agonist Reduces Atherosclerotic Plaque And Prevents Hepatotoxicity
Authors: Chhaya Vina Y , Maragos Sophia , Qiu Ruomeng , Egner Simon A , Karver Mark R , Stupp Samuel I , Tsihlis Nick D , Kibbe Melina R
Published: October 2023

Cardiovascular disease remains a leading cause of global morbidity and mortality. Nanotechnology offers a unique approach to treat atherosclerosis by targeting therapeutics to sites of interest, thereby avoiding side effects from systemic administration. A liver X receptor (LXR) α agonist, GW3965, was modified to create a drug-peptide conjugate (GW3965-V
2
A
2
E
2
) and co-assembled with a peptide amphiphile (PA) nanofiber displaying an apolipoprotein A1 (ApoA1)-mimetic sequence to target atherosclerotic plaque. A range of molar equivalents of GW3965-V
2
A
2
E
2
was co-assembled with the ApoA1-targeted PA nanofibers to investigate secondary structure motifs and supramolecular structure, with 0.5 molar equivalents showing optimal therapeutic loading. Further
in vitro
testing demonstrated up to 92% release of GW3965-V
2
A
2
E
2
from the nanofibers as quantified by mass spectrometry, and a critical aggregation concentration of <0.1μM for the ApoA1-GW3965 nanofibers. After 4 weeks of tail vein injections (twice/week) in low-density lipoprotein receptor knockout mice, atherosclerotic plaque size was significantly reduced by ApoA1-GW3965 nanofiber compared to controls (14% vs. 17%,
p
≤ 0.01). Furthermore, we observed sex differences in the development of atherosclerosis. Male mice in the control group had greater plaque size compared to females (18.5% vs. 15.1%,
p
≤ 0.02). Importantly, there was a reduction in plaque size in male mice treated with ApoA1-GW3965 nanofibers compared to male controls (13.2% vs. 18.5%,
p
≤ 0.0001), whereas female mice across treatment groups demonstrated no significant change. Mice treated with ApoA1-GW3965 nanofibers showed no difference in hepatosteatosis compared to controls (34.7% vs. 36.9%,
p
= 0.13) and equivalent liver enzymes (AST, ALT, and ALP,
p
= not significant), suggestive of less hepatocyte injury in mice given the LXR agonist. In conclusion, these data demonstrate the development of an ApoA1-targeted nanotherapeutic using non-covalent incorporation of a drug-peptide conjugate with therapeutic efficacy in atherosclerotic plaque reduction. Given the known hepatotoxicity when LXR agonists are administered systemically, this work shows great promise for the targeted delivery of GW3965 for plaque reduction.
Abstract 135: The Aim2 Inflammasome Deters Myogenic Potential Of Muscle Satellite Cells Affected By Peripheral Artery Disease (pad) And Is A Therapeutic Target To Attenuate Myopathy
Authors: Xie Bowen , Assaf Edwyn , Ferrari Ricardo , Kulkarni Rohan , McEnaney Ryan , Sachdev Ulka
Published: October 2023

Introduction:
We showed that myoblasts (Mb) in PAD have poor fusion capacity needed for regeneration. High expression of the absent in melanoma 2 (AIM2) inflammasome correlated with this finding. AIM2 responds to damaged DNA and mediates pyroptosis, an inflammatory form of programmed cell death. Yet, AIM2 has not been studied as a target to reduce PAD muscle damage. We hypothesize that compared to other nucleic acid sensors, AIM2 is the key mediator of damage in ischemic Mb, and a novel target to reduce PAD myopathy.

Methods:
Mb were obtained from perfused and ischemic muscle during PAD-related operations. Mb (Pax7-/MyoD+) were isolated using sequential plating and cell sorting or were purchased (Cook Myosite). Myocyte fusion index (MFI) was measured in cells ± the dsDNA mimetic poly
(dA:dT)
in transfection reagent ± short inhibitory (si)RNA to AIM2, toll-like receptor (TLR9), cyclic GMP-AMP synthase (cGAS) or nonspecific control target. Rate of apoptosis was measured using live-cell imaging detecting caspases-3 and -7 over time. Wildtype (WT), and AIM2KO mice underwent unilateral femoral artery ligation (FAL), and perfusion recovery was measured at 3wks. ANOVA with post-hoc analysis confirmed statistical significance (α=0.05)

Results:
Poly
(dA:dT)
decreased MFI across MuSC groups (N=3-4/group, 5 images each, p<0.0001). siRNA against AIM2 but not TLR9, cGAS or a nonspecific target increased MFI in PAD myoblasts (N=4-8/group, p<0.0001) and reversed poly
(dA:dT)
fusion inhibition. AIM2 inhibition also reduced Mb apoptosis (p<0.0001; Fig 1). AIM2KO and WT mice had similar perfusion recovery (p=0.65) after FAL suggesting that potential myogenic differences occur independent of perfusion.

Conclusion:
Specific inhibition of the AIM2 inflammasome improves the myogenic properties of Mb from PAD affected muscle including fusion capacity and viability. AIM2 is a target for novel therapeutics to reduce myopathy and potentially improve function in PAD
Abstract 140: A Common, Racially Diverse Protease Activated Receptor 4 Functional Variant Impacts Ischemic Stroke Outcomes: Evidence For A Pharmacogenetic Effect
Authors: Denorme Frederik , Armstrong Nicole D , Stoller Michelle , Portier Irina , Tugolukova Emilia , Tanner Rikki M , Bhatlekar Seema , Cody Mark , Rustad John , Nieman Marvin T , McKenzie Steven E , Yost Christian , Lange Leslie , Cushman Mary , Irvin Marguerite M , Bray Paul F , Campbell Robert
Published: October 2023

Black individuals have a higher incidence of ischemic stroke (IS) than White individuals. The platelet receptor PAR4 harbors a functional dimorphism: rs773902 A/G (encoding Thr120/Ala120, respectively), and the A allele is associated with greater
ex vivo
platelet aggregation. The A allele frequency is 0.6 in Black individuals and 0.2 in White subjects. However, it is unknown whether the A allele contributes to racial differences in IS. In a prospective cohort, the REGARDS study, a Black subject-only analysis of 487 IS cases and 7,133 controls was performed, examining if the A allele was a risk for incident IS and worse IS outcome. We used Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of incident IS for the rs773902 A allele. Models were adjusted for age, sex, the first 5 genetic principal components, smoking, hypertension and diabetes. To directly test the effect of this PAR4 variant on IS, we generated the first humanized PAR4 (hPAR4) mouse strains expressing either hPAR4 Thr120 or hPAR4 Ala120. In REGARDS, the A allele was a risk factor for incident IS (HR 1.24; CI 1.04-1.53, p=0.046) and worse IS outcome (HR 2.04; CI 1.10-3.79, p=0.025). In a murine stroke model, hPAR4 Thr120 mice had worse stroke outcomes compared to hPAR4 Ala120 mice (60% increase, p=0.001). This phenotype was mediated, in part, by enhanced platelet activation (p=0.002), platelet-neutrophil interactions (p=0.014), and neutrophil extracellular traps (p=0.001). Direct inhibition of PAR4 with BMS-986120 was equally effective in improving stroke outcomes in hPAR4 Ala120 and Thr120 mice. In contrast, ticagrelor treatment improved stroke outcomes in hPAR4 Ala120 mice (50% decrease, p=0.007), but was ineffective in hPAR4 Thr120 mice, even when combined with aspirin. Importantly, blocking platelet-neutrophil interactions downstream of PAR4 with a murine analog of the FDA-approved P-selectin inhibitor crizanlizumab improved stroke outcomes in hPAR4 Thr120 mice (55% decrease, p=0.004). These results support a causal role for PAR4 Thr120 in IS that may explain part of the racial disparity in stroke. Our findings further suggest that different anti-platelet therapies may be needed for patients expressing PAR4 Thr120.