bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB521: Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis
Authors: Hwang Kwangwoo , Jo SeoHyun , Choi Jieun , Choi Ga-young , Choi Jiseon , Kwon Ji-Hye , Shin Dong-Guk , Kim Jiyeon , Kim Se-Hyuk , Kim Haelee , Cho Ha Yeon , Son Jung Beom , Kim Nam Doo , Choi Hwan Geun , Kim Daekwon , Kim Sunghwan 
Published: June 2022

Abstract
FDA approved three RAF inhibitors for the treatment of tumors containing BRAFV600 mutations, but one of the major drawbacks of these type I RAF inhibitors is to activate MAPK signaling pathway, instead of inhibiting signaling, which is referred to as paradoxical activation. Such undesired paradoxical activation not only leads to renewed tumor growth but also spurs additional cancer growth in non-cancerous wild-type BRAF tissue. Plus, these first-generation RAF inhibitors targeting BRAFV600 mutants are unable to inhibit oncogenic RAF dimers. This has led to the development of type II RAF inhibitors such as belvarafenib and day101 to block the activity of multiple forms of RAF while avoiding paradoxical activation. Two lead-like stage compounds 1 and 2 were specifically designed as type II RAF inhibitors to have activity across RAF isoforms including BRAFV600E, BRAF wild-type, and CRAF, showing higher potency than competitors. Compounds 1 and 2 potently inhibited the growth of BRAFV600E melanoma cells and NRAS or KRAS mutant cancer cells. Compounds 1 and 2 promoted the formation of BRAF/CRAF heterodimers by directly binding to the RAF kinase domain like other type II RAF inhibitors and inhibited phosphorylation of downstream effectors MEK and ERK in a dose-dependent manner in RAS mutant cancer cells, suggesting less paradoxical activation liability. Compound 2 showed superior on-target inhibitory activity for BRAFV600E, BRAF wild-type, and CRAF than belvarafenib through RAF immunoprecipitation (IP) kinase assay. Inhibition of the RAF downstream signaling was also confirmed by quantifying the level of phospho-ERK in NRAS or KRAS mutant cancer cells. In HCT116 (KRASG13D) subcutaneous xenograft model, compound 1 showed tumor growth inhibition efficacy, suggesting a potential to address RAS mutant driven- as well as BRAFV600 mutant driven tumors. Also, combination treatment with MEK inhibitor and/or immune checkpoint inhibitor would further improve the therapeutic activity and expand target indication for unmet medical needs.
Citation Format: Kwangwoo Hwang, SeoHyun Jo, Jieun Choi, Ga-young Choi, Jiseon Choi, Ji-Hye Kwon, Dong-Guk Shin, Jiyeon Kim, Se-Hyuk Kim, Haelee Kim, Ha Yeon Cho, Jung Beom Son, Nam Doo Kim, Hwan Geun Choi, Daekwon Kim, Sunghwan Kim. Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB521.
Abstract LB535: A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer
Authors: Nadal Lisa , Peissert Frederik , Elsayed Abdullah , Libbra Chiara , Neri Dario , De Luca Roberto 
Published: June 2022

Abstract
Immunocytokines, which consist of the fusion of cytokines to tumor targeting antibodies, represent a novel class of biopharmaceuticals that have great potential for cancer treatment. The use of these products improves the efficacy of the delivered drug by reducing related side effects and significantly enhances the therapeutic index of the payload. Over the past years, nuclear medicine studies have validated the Fibroblast Activation Protein (FAP) as a pantumoral antigen, with more than 28 different cancer types successfully imaged in patients. Since FAP is mostly undetectable in healthy organs, it has been considered as an attractive target for both imaging and therapeutic applications. For this reason, here we describe the generation of a novel fully human monoclonal antibody targeting FAP. The antibody was isolated from a synthetic antibody phage display library and its tumor recognition properties were validated by immunofluorescence performed on a commercial tissue microarray as well as on freshly frozen colon cancer biopsies from human patients. An ex vivo biodistribution analysis in mice confirmed the ability of anti-FAP in IgG1 format to selectively localize to solid tumors while sparing healthy organs. Furthermore, Pharmacokinetics (PK) studies in Cynomolgus Monkey showed no sink effects at early time points and a slow clearance from bloodstream as expected for IgG1 antibodies. Encouraged by these results, an antibody cytokine fusion (mIL12-FAP) based on the novel anti-FAP antibody was generated and characterized in vitro and in vivo, showing activation of the immune system both in immunocompetent and immunodeficient mouse models bearing FAP-positive tumors. mIL12-FAP exhibited strong anticancer activity in mice bearing CT26-FAP colon carcinomas which could be boosted by the combination with immune checkpoint inhibitors, leading to durable cancer eradication. The targeted delivery of mIL12 to the tumor microenvironment increased the infiltrate of tumor-specific lymphocytes and Natural Killer (NK) cells as compared to the control group without apparent evidence of toxicity.
Citation Format: Lisa Nadal, Frederik Peissert, Abdullah Elsayed, Chiara Libbra, Dario Neri, Roberto De Luca. A novel IL12-based immunocytokine targeting fibroblast activation protein (FAP) for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB535.
Abstract LB549: LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer
Authors: Gao Yanping , Zhang Nannan , Gong Yan , Xie Conghua 
Published: June 2022

Abstract
Background: The long non-coding RNA (lncRNA) PCAT1 is upregulated in non-small cell lung cancer (NSCLC), and promotes tumor growth and metastasis, but its roles in the radioimmune responses remain unknown. We aimed to investigate the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC.
Methods: Comprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumor invasion in NSCLC. The expression levels of PCAT1 were analyzed by in situ hybridization in 55 paired NSCLC and adjacent normal tissues. Both loss- and gain-of-function assays were performed to evaluate the functions of PCAT1 and SOX2 in NSCLC cell behaviors in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification and dual-luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase, and rescue assays were utilized to identify the relationship between SOX2 and the cGAS/STING signaling.
Results: PCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and inhibited cell migration and invasion in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumor growth through inhibiting cytotoxic T cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I IFN-induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumor growth, and activated the cGAS/STING signaling pathway, which enhanced the immune responses of radiotherapy in NSCLC.
Conclusions: PCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signaling-mediated T-cell activation. Inhibition of PCAT1 and SOX2 synergized with radiotherapy to activate the immune response and could serve as potential therapeutic targets.
Citation Format: Yanping Gao, Nannan Zhang, Yan Gong, Conghua Xie. LncRNA PCAT1 activates SOX2 and suppresses radioimmune responses via regulating cGAS/STING signaling in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB549.
Abstract LB557: Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition
Authors: Martin John , Lanning Ryan , Fukumura Dai , Padera Timothy , Jain Rakesh 
Published: June 2022

Abstract
Purpose: The abnormal function of tumor blood vessels causes hypoxia fueling disease progression and conferring treatment resistance. The local level of oxygen experienced by a cell will determine its response, making it critical to understand tissue oxygen levels with a spatial resolution on the order of the size of a cell. While microenvironment normalization strategies alleviate global hypoxia, how local oxygen levels change are not known because there are no in vivo techniques to longitudinally assess tumor vessels and interstitial oxygen in tumors with sufficient resolution. Understanding the heterogeneity of oxygen levels after microenvironmental normalization will help improve the efficacy of various normalization strategies.
Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and tumors. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to microenvironmental normalization.
Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors coincided with heterogeneous response to microenvironmental normalizing agents. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with global reductions in hypoxia.
Conclusions: We present the first study to examine the high-resolution spatial and temporal response of tumor vessels to two agents known to improve vascular perfusion globally. Our measurements demonstrate that the heterogeneities in the local imbalance of pro- and anti-angiogenic signaling lead to spatially heterogeneous changes in vessel structure and function. Microscale dynamic vascular changes should be considered in optimizing the dose and schedule of microenvironment normalizing therapies to improve function.
Citation Format: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain. Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB557.
Risk factors for asthma exacerbations during pregnancy: a systematic review and meta-analysis
Authors: Robijn Annelies L. , Bokern Marleen P. , Jensen Megan E. , Barker Daniel , Baines Katherine J. , Murphy Vanessa E. 
Published: June 2022

BackgroundConflicting literature exists regarding the risk factors for exacerbations among pregnant women with asthma. This systematic review and meta-analysis aimed to determine risk factors for asthma exacerbations during pregnancy.MethodsElectronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*) and (exacerb* or flare up or morbidit* or attack*).All studies published between 2000 and 24 August 2021 were considered for inclusion if they reported at least one potential risk factor of asthma exacerbations in pregnant women with asthma. Of the 3337 references considered, 35 publications involving 429 583 pregnant women with asthma were included. Meta-analyses were conducted to determine mean difference in risk factor between exacerbation groups, or the relative risks of exacerbation with certain risk factors. Good study quality was found through the Newcastle-Ottawa Scale (median score 8, interquartile range 7–9).ResultsIncreased maternal age (mean difference 0.62, 95% CI 0.11–1.13), obesity (relative risk 1.25, 95% CI 1.15–1.37), smoking (relative risk 1.35, 95% CI 1.04–1.75), black ethnicity (relative risk 1.62, 95% CI 1.52–1.73), multiparity (relative risk 1.31, 95% CI 1.01–1.68), depression/anxiety (relative risk 1.42, 95% CI 1.27–1.59), moderate–severe asthma (relative risk 3.44, 95% CI 2.03–5.83,versusmild) and severe asthma (relative risk 2.70, 95% CI 1.85–3.95,versusmild–moderate) were associated with an increased risk of asthma exacerbations during pregnancy.ConclusionsFuture interventions aimed at reducing exacerbations in pregnancy could address the modifiable factors, such as smoking and depression/anxiety, and introduce more regular monitoring for those with nonmodifiable risk factors such as obesity and more severe asthma.
Suitability of accelerometry as an objective measure for upper extremity use in stroke patients
Authors: Heye Anne-Lisa , Kersting Christine , Kneer Malte , Barzel Anne 
Published: June 2022

Abstract
Background
Upper limb (UL) paresis is one of the most common stroke consequences and significantly restricts patients in everyday life. Instruments objectively measuring direct arm use in stroke patients are lacking, but might be helpful to understand patients’ impairment. Aiming to examine whether accelerometry is a suitable objective measure for everyday UL use in stroke patients, we conducted a systematic review on the association between accelerometer-derived measurements and clinical scales.

Methods
Articles were systematically searched in PubMed, Scopus, Cochrane Library, PeDro and LIVIVO through December 12th, 2021, screened for inclusion by AH, and subsequently independently screened by CK and MK. Disagreements were discussed until consensus. We included English and German peer-reviewed articles dealing with the validity of accelerometers as a measurement of UL use in stroke patients and eligible systematic reviews. Studies exclusively using accelerometry as an outcome parameter, book contributions, conference abstracts and case studies were excluded. Data extraction was conducted by AH and confirmed by CK focussing on study type, objective, accelerometer device, sample size, stroke status, assessments conducted, measurement method, wearing time and key results. We analysed all eligible articles regarding the correlation between accelerometry and other clinical assessments and the validity in accordance with the type of accelerometer.

Results
Excluding duplicates, the initial search yielded 477 records. In the 34 eligible studies accelerometers was used with a predominance of tri-axial accelerometery (n = 12) and only few with two-axial application (n = 4). Regarding measures to examine association to accelerometer data different clinical scales were applied depending on the setting, the degree of impairment and/or the status of stroke. Cut-off values to determine correlations varied largely; most significant correlations are reported for the MAL [Range 0.31- 0.84] and the ARAT [Range 0.15–0.79].

Conclusions
Accelerometers can provide reliable data about daily arm use frequency but do not supply information about the movements´ quality and restrictions on everyday activities of stroke patients. Depending on the context, it is advisable to use both, accelerometry and other clinical measures. According to the literature there is currently no accelerometer device most suitable to measure UL activity. High correlations indicate that multi-dimensional accelerometers should be preferred.
Hiccups in patients with cancer: a multi-site, single-institution study of etiology, severity, complications, interventions, and outcomes
Authors: Ehret Christopher J. , Almodallal Yahya , Le-Rademacher Jennifer G. , Martin Nichole A. , Moynagh Michael R. , Rajotia Arush , Jatoi Aminah 
Published: June 2022

Abstract
Background
To our knowledge, previous studies have not investigated hiccups in patients with cancer with detailed patient-level data with the goal of capturing a broad spectrum of hiccup symptomatology.

Methods
This multi-site, single institution study examined consecutive medical records to better understand hiccups in patients with cancer.

Results
A total of 320 patients are the focus of this report. The median age of patients when hiccups were first reported in the medical record was 63 years (range: 21, 97 years) with 284 (89%) men and 36 (11%) women. The most common diagnose was gastrointestinal cancer. Hiccups most frequently occurred daily, as seen in 194 patients (62%), and the most common duration was less than 1 week, as seen in 146 patients (47%). However, nine patients had had daily hiccups for greater than 6 weeks, and 5 had symptoms for years. Cited etiology was non-chemotherapy medications in 36 (11%) and cancer chemotherapy in 19 (6%). Complications occurred in approximately a third and included insomnia in 51 patients (16%); hospitalization or emergency department visit in 34 (11%); and musculoskeletal pain in 23 (7%). Baclofen was the single most prescribed agent for hiccup palliation, but 100 patients received more than one medication. Medical procedures, which included acupuncture, paracentesis, or phrenic nerve block, were performed in 5 patients. In 234 patients (73%), the medical record documented hiccup cessation.

Conclusions
Hiccups appear to be highly problematic in a small subset of patients with cancer with no well-defined palliative approaches.
Prevalence and determinants of aggressive behavior among adults with problematic substance use in Northwest Ethiopia: a cross-sectional survey
Authors: Legas Getasew , Belete Habte , Asnakew Sintayehu 
Published: June 2022

Abstract
Background
The recent WHO data reported that a high treatment gap for behavioral illnesses (70%) in low- and- middle-income countries and the mortality rate of aggressive behavior reaches up to 32.1 per 100,000 populations in the region. However, the magnitude of aggressive behavior is not well stated in resource-limited settings. Therefore, the aim of this study was to assess the prevalence and determinant factors of aggressive behavior among adults with problematic substance use in northwest Ethiopia.

Methods
A community-based cross-sectional study was employed from January to March 2019. A multi-stage cluster sampling method was used to screen a total of 4028 adults for problematic substance use by using the Cutdown, Annoyed, Guilty, and Eye-opener questionnaire (CAGE AID). Finally, 838 participants were positive for problematic substance use and interviewed for aggressive behavior using a modified overt aggression scale. Multiple logistic regression analysis was used to show the adjusted odds ratios (AOR) and p-value < 0.05 considered statistically significant. A multilevel binary logistic regressions model was employed for the hierarchical structure of two-level data for the individual and woreda/district levels.

Results
The prevalence of aggressive behavior was found to be 37.9% (301/795, 95% CI: 34.5, 41.3). Stressful life events (AOR = 2.209, 95 CI; 1.423, 3.429), family history of mental illness (AOR = 4.038, 95 CI; 2.046, 7.971), comorbid physical illness (AOR = 2.01, 95 CI; 1.332, 3.032) and depressive symptoms (AOR = 2.342, 95 CI; 1.686, 3.253) were associated with aggressive behavior among individual with problem substance use.

Conclusion
Aggressive behavior was found to be high among problematic substance uses. An individual with problematic substance use is recommended to be screened by health extension workers for aggressive behavior at the community level.
Neighborhood social cohesion and serious psychological distress among Asian, Black, Hispanic/Latinx, and White adults in the United States: a cross-sectional study
Authors: Gullett Lauren R. , Alhasan Dana M. , Gaston Symielle A. , Jackson W. Braxton , Kawachi Ichiro , Jackson Chandra L. 
Published: June 2022

Abstract
Background
Serious psychological distress (SPD) is common and more prevalent in women, older adults, and individuals with a low-income. Prior studies have highlighted the role of low neighborhood social cohesion (nSC) in potentially contributing to SPD; however, few have investigated this association in a large, nationally representative sample of the United States. Therefore, our objective was to investigate the overall and racial/ethnic-, sex/gender-, self-rated health status-, age-, and household income-specific relationships between nSC and SPD.

Methods
We used data from survey years 2013 to 2018 of the National Health Interview Survey to investigate nSC and SPD among Asian, Non-Hispanic (NH)-Black, Hispanic/Latinx, and NH-White men as well as women in the United States (N = 168,573) and to determine modification by race/ethnicity, sex/gender, self-rated health status, age, and annual household income. nSC was measured by asking participants four questions related to the trustworthiness and dependability of their neighbors. nSC scores were trichotomized into low (< 12), medium (12–14), and high (15–16). SPD was measured using the Kessler 6 psychological distress scale with scores ≥ 13 indicating SPD. After adjusting for sociodemographic, health behavior, and clinical confounders, we used Poisson regression with robust variance to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs).

Results
Among 168,573 participants, most were Non-Hispanic (NH)-White (69%), and mean age was 47 ± 0.01 years. After adjustment, low vs. high nSC was associated with a 75% higher prevalence of SPD overall (PR = 1.75 [1.59–1.92]), 4 times the prevalence of SPD among Asian men (PR = 4.06 [1.57–10.50]), 2 times the prevalence of SPD among participants in at least good health (PR = 2.02 [95% CI: 1.74–2.35]), 92% higher prevalence of SPD among participants ≥ 50 years old (PR = 1.92 [1.70–2.18]), and approximately 3 times the prevalence of SPD among Hispanic/Latinx participants with household incomes ≥ $75,000 (PR = 2.97 [1.45–6.08]).

Conclusions
Low nSC was associated with higher SPD in the overall population and the magnitude of the association was higher in Asian men, participants who reported good health, older participants, and Hispanic/Latinx adults with higher household incomes. Future research should continue to examine how neighborhood contexts can affect health across various sociodemographic groups, especially among groups with multiple marginalized social identities.