tbuckley/cabot-search huggingface dataset:
Thrombospondin-1 Plays a Major Pathogenic Role in Experimental and Human Bronchopulmonary Dysplasia
Authors: Brittany Ann Ruschkowski, Yousef Esmaeil, Kate Daniel, Chantal Gaudet, Behzad Yeganeh, David Grynspan, Robert P. Jankov
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Extremely preterm infants develop bronchopulmonary dysplasia (BPD), a chronic lung injury that lacks effective treatment. TSP-1 (thrombospondin-1) is an antiangiogenic protein that activates TGF-β1 (transforming growth factor-β1), a cytokine strongly linked to both experimental and human BPD. Objectives:1) To examine effects of inhibiting TSP-1-mediated TGF-β1 activation (LSKL [leucine-serine-lysine-leucine]) in neonatal rats with bleomycin-induced lung injury; 2) to examine effects of a TSP-1 mimic (ABT-510) on lung morphology; and 3) to determine whether TSP-1 and related signaling peptides are increased in lungs of human preterm infants at risk for BPD. Methods: From Postnatal Days 1 to 14, rat pups received daily intraperitoneal bleomycin (1 mg/kg) or vehicle and were treated with daily subcutaneous LSKL (20 mg/kg) or vehicle alone. Separate animals were treated with vehicle or ABT-510 (30 mg/kg/d). Paraffin-embedded lung tissues from 47 autopsies (controls; death <28 d, n = 30 and BPD at risk; death ⩾28 d, n = 17) performed on infants born <29 completed weeks' gestation were semiquantified for injury markers (collagen, macrophages, and 3-nitrotyrosine), TSP-1, and TGF-β1. Measurements and Main Results: Bleomycin or ABT-510 increased lung TGF-β1 activity and macrophage influx, caused pulmonary hypertension, and led to alveolar and microvascular hypoplasia. Treatment with LSKL partially prevented abnormal lung morphology secondary to bleomycin. Lungs from human infants at risk for BPD had increased contents of TSP-1 and TGF-β1 when compared with controls. TGF-β1 content correlated with markers of lung injury. Conclusions: TSP-1 inhibits alveologenesis in neonatal rats, in part via the upregulated activity of TGF-β1. Observations in human lungs suggest a similar pathogenic role for TSP-1 in infants at risk for BPD.
Cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia after a second ChAdOx1 nCoV-19 dose
Authors: Katarzyna Krzywicka, Anita van de Munckhof, Julian Zimmermann, Felix J. Bode, Giovanni Frisullo, Theodoros Karapanayiotides, Bernd Pötzsch, Mayte Sánchez van Kammen, Mirjam R. Heldner, Marcel Arnold, Johanna A. Kremer Hovinga, José M. Ferro, Diana Aguiar de Sousa, Jonathan M. Coutinho
Journal: Blood (2022)

Vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare but life-threatening complication of adenoviral vaccination against COVID-19, has been reported almost entirely following the first dose. Krzywicka and colleagues report on 124 patients with VITT in a multinational registry diagnosed after dose 2; no specific events were observed after dose 1. These patients had early presentation, and two of the patients died.
Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus
Authors: Yusuke Takeshima, Yukiko Iwasaki, Masahiro Nakano, Yuta Narushima, Mineto Ota, Yasuo Nagafuchi, Shuji Sumitomo, Tomohisa Okamura, Keith Elkon, Kazuyoshi Ishigaki, Akari Suzuki, Yuta Kochi, Kazuhiko Yamamoto, Keishi Fujio
Journal: Annals of the Rheumatic Diseases (2022)

Objective Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease. While the long-term prognosis has greatly improved, better long-term survival is still necessary. The type I interferon (IFN) signature, a prominent feature of SLE, is not an ideal therapeutic target or outcome predictor. To explore immunological pathways in SLE more precisely, we performed transcriptomic, epigenomic and genomic analyses using 19 immune cell subsets from peripheral blood. Methods We sorted 19 immune cell subsets and identified the mRNA expression profiles and genetic polymorphisms in 107 patients with SLE and 92 healthy controls. Combined differentially expressed genes and expression quantitative trait loci analysis was conducted to find key driver genes in SLE pathogenesis. Results We found transcriptomic, epigenetic and genetic importance of oxidative phosphorylation (OXPHOS)/mitochondrial dysfunction in SLE memory B cells. Particularly, we identified an OXPHOS-regulating gene, PRDX6 (peroxiredoxin 6), as a key driver in SLE B cells. Prdx6- deficient B cells showed upregulated mitochondrial respiration as well as antibody production. We revealed OXPHOS signature was associated with type I IFN signalling-related genes (ISRGs) signature in SLE memory B cells. Furthermore, the gene sets related to innate immune signalling among ISRGs presented correlation with OXPHOS and these two signatures showed associations with SLE organ damage as well as specific clinical phenotypes. Conclusion This work elucidated the potential prognostic marker for SLE. Since OXPHOS consists of the electron transport chain, a functional unit in mitochondria, these findings suggest the importance of mitochondrial dysfunction as a key immunological pathway involved in SLE.
Abstract P1-24-01: Does modified radical mastectomy in de novo stage IV inflammatory breast cancer patients improve disease specific survival?
Authors: JC Chen, Yaming Li, James L. Fisher, Allan Tsung, Samilia Obeng-Gyasi
Journal: Cancer Research (2022)

Abstract Introduction: Inflammatory breast cancer (IBC) is an aggressive breast cancer subtype with poor prognosis. In the non-metastatic setting, the current literature suggests modified radical mastectomy (MRM) in conjunction with chemotherapy and radiation therapy improve clinical outcomes. However, for de novo metastatic IBC patients, surgical management is mostly palliative, and little is known about its implications for survival. The objective of this study is to evaluate the association between MRM and disease specific survival (DSS) among a contemporary cohort of de novo stage IV IBC patients. Methods: The Surveillance, Epidemiology and End Results (SEER) Program was queried for IBC (T4d) patients diagnosed between 2010-2016. The study cohort was divided into two groups- MRM vs no MRM. Surgical management was limited to patients who underwent MRM. Bivariable analysis was conducted to compare sociodemographic and clinical variables between the groups. The surgery group was nearest matched to the no-surgery group (1:2) on age, year of diagnosis, location of metastasis (e.g., bone only), number of metastatic sites, breast cancer subtype, chemotherapy and radiation therapy. A Kaplan-Meier curve was used to evaluate DSS between the two groups in the matched sample. Results: Of the 1293 patients who met study criteria, 240 underwent MRM and 1053 had no surgery. Patients undergoing MRM were more likely to be younger (MRM 55.7years±13.5, no MRM 59.40years±13.4; p&amp;lt;0.001), have poorly differentiated tumors (grade 3; MRM 63.7%, no MRM 46.7%; p&amp;lt;0.001) and metastasis in only one organ site (MRM 69.8%, no MRM 52.2%; p&amp;lt;0.001). On matched analysis, patients who underwent MRM had longer DSS than those who did not undergo surgery (p=0.001). Moreover, the 5-year survival rate for surgical patients was 31.4% compared to 17.7% for the no surgery group. The median survival time was 38 months for patients who underwent MRM (interquartile range [IQR] 27-45 months] compared to 27 months (22-29 months) among those who did not have surgery. Conclusion: In this SEER cohort of de novo metastatic IBC patients, MRM was associated with an improved disease specific survival compared to no surgery. These results suggest surgical management should be considered in this population. Future prospective studies are needed to better define which subset of de novo metastatic IBC patients derive the most benefit from surgery, and consequently, should routinely undergo surgery. Citation Format: JC Chen, Yaming Li, James L. Fisher, Allan Tsung, Samilia Obeng-Gyasi. Does modified radical mastectomy in de novo stage IV inflammatory breast cancer patients improve disease specific survival? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-01.
Dimethylamino group modified polydopamine nanoparticles with positive charges to scavenge cell-free DNA for rheumatoid arthritis therapy
Authors: Ying Chen, Yonglin Wang, Xianfang Jiang, Jinhong Cai, Yuting Chen, Hanji Huang, Yuan Yang, Li Zheng, Jinmin Zhao, Ming Gao
Journal: Bioactive Materials (2022)

Excessive cell-free DNA (cfDNA) released by damaged or apoptotic cells can cause inflammation, impacting the progression of rheumatoid arthritis (RA). cfDNA scavengers, such as cationic nanoparticles (NPs), have been demonstrated as an efficient strategy for treating RA. However, most scavengers are limited by unfavorable biocompatibility and poor scavenging efficacy. Herein, by exploiting the favorable biocompatibility, biodegradability and bioadhesion of polydopamine (P), we modified P with dimethylamino groups to form altered charged DPs to bind negatively charged cfDNA for RA therapy. Results showed that DPs endowed with superior binding affinity of cfDNA and little cytotoxicity, which effectively inhibited lipopolysaccharide (LPS) stimulated inflammation in vitro, resulting in the relief of joint swelling, synovial hyperplasia and cartilage destruction in RA rats. Significantly, DPs with higher DS of bis dimethylamino group exhibited higher positive charge density and stronger cfDNA binding affinity, leading to excellent RA therapeutic effect among all of the treated groups, which was even close to normal rats. These finding provides a novel strategy for the treatment of cfDNA-associated diseases.
Abstract P1-08-06: Development of an aritifical neural network model and comparison with nomogram for prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer
Authors: Hee-Chul Shin, Ji-Jung Jung, Eun-Kyu Kim, Eunyoung Kang
Journal: Cancer Research (2022)

Abstract Purpose: Identifying patients who may benefit from neoadjuvant chemotherapy will facilitate personalized treatment regarding chemotherapy and surgery. This study compares the predictive performance of an artificial neural network algorithm with nomogram to predict pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with advanced breast cancer.. Methods: Medical records of 359 patients with advanced breast cancer who received NAC prior to surgical resection between January 2017 and December 2019 were retrospectively reviewed. Random over sampling method was used to overcome data imbalance and random sampling method to divide patients into training and test sets at a split ratio of 7:3. Univariate and multivariate regression analyses were used to develop a nomogram and a machine learning model based on artificial neural network. Performance of the two models were evaluated using the validation sets in terms of area under the receiver operating characteristic curve (AUC).. Results: Multivariate logistic regression analysis showed that high level of estrogen receptor (ER) (OR 0.84, p &amp;lt; 0.001), positive human epidermal growth factor receptor 2 (HER2) status (OR 1.25, p &amp;lt; 0.001), complete response on magnetic resonance imaging (MRI) (OR 1.62, p &amp;lt; 0.001), abnormal CEA level after NAC (OR 0.86, p = 0.051), and abnormal CA15-3 level after NAC (OR 0.87, p = 0.074) were independent predictors of pCR. A nomogram and a neural network model to predict pCR were developed using the five predictors. Validation test showed AUCs of 0.789 [95 % confidence interval (CI), 0.707-0.871] for the nomogram and 0.876 [95 % CI, 0.808-0.943] for the neural network model.. Conclusion: We developed a nomogram and an artificial neural network (ANN)-based machine learning model to predict pCR after NAC. Both models showed excellent performance, but the ANN model performed better in terms of accuracy and discrimination. Machine-learning algorithms hold promise in medical application and provide better prediction than nomogram. Citation Format: Hee-Chul Shin, Ji-Jung Jung, Eun-Kyu Kim, Eunyoung Kang. Development of an aritifical neural network model and comparison with nomogram for prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-06.
Increasing the diversity of dietary fibers in a daily-consumed bread modifies gut microbiota and metabolic profile in subjects at cardiometabolic risk
Authors: Harimalala Ranaivo, Florence Thirion, Christel Béra-Maillet, Susie Guilly, Chantal Simon, Monique Sothier, Laurie Van Den Berghe, Nathalie Feugier-Favier, Stéphanie Lambert-Porcheron, Isabelle Dussous, Loïc Roger, Hugo Roume, Nathalie Galleron, Nicolas Pons, Emmanuelle Le Chatelier, Stanislav Dusko Ehrlich, Martine Laville, Joël Doré, Julie-Anne Nazare
Journal: Gut Microbes (2022)

Some cardiometabolic risk factors such as dyslipidemia and insulin resistance are known to be associated with low gut microbiota richness. A link between gut microbiota richness and the diversity of consumed dietary fibers (DF) has also been reported. We introduced a larger diversity of consumed DF by using a daily consumed bread in subjects at cardiometabolic risk and assessed the impacts on the composition and functions of gut microbiota as well as on cardiometabolic profile. Thirty-nine subjects at cardiometabolic risk were included in a double-blind, randomized, cross-over, twice 8-week study, and consumed daily 150 g of standard bread or enriched with a 7-dietary fiber mixture (5.55 g and 16.05 g of fibers, respectively). Before and after intervention, stool samples were collected for gut microbiota analysis from species determination down to gene-level abundance using shotgun metagenomics, and cardiometabolic profile was assessed. Multi-fiber bread consumption significantly decreased Bacteroides vulgatus, whereas it increased Parabacteroides distasonis, Fusicatenibacter saccharivorans, an unclassified Acutalibacteraceae and an unclassified Eisenbergiella (q < 0.1). The fraction of gut microbiota carrying the gene coding for five families/subfamilies of glycoside hydrolases (CAZymes) were also increased and negatively correlated with peaks and total/incremental area under curve (tAUC/iAUC) of postprandial glycemia and insulinemia. Compared to control bread, multi-fiber bread decreased total cholesterol (−0.42 mM; q < 0.01), LDL cholesterol (−0.36 mM; q < 0.01), insulin (−2.77 mIU/l; q < 0.05), and HOMA (−0.78; q < 0.05). In conclusion, increasing the diversity of DF in a daily consumed product modifies gut microbiota composition and function and could be a relevant nutritional tool to improve cardiometabolic profile.
CLO22-052: A Tale of Two Schedules: A Study of the Efficacy and Toxicity Outcomes of Extended Durvalumab Dosing in Patients with Stage III Unresectable Non-Small Cell Lung Cancer (NSCLC)
Authors: Lilian Hanna, Gordon Taylor Moffat, Wilma Hopman, Pierre-Olivier Gaudreau, Andrea S. Fung
Journal: Journal of the National Comprehensive Cancer Network (2022)

"CLO22-052: A Tale of Two Schedules: A Study of the Efficacy and Toxicity Outcomes of Extended Durvalumab Dosing in Patients with Stage III Unresectable Non-Small Cell Lung Cancer (NSCLC)" published on 31 Mar 2022 by National Comprehensive Cancer Network.
Parish level social factors predict population-based cervical cancer incidence in Kampala, Uganda, 2008–15: an ecological study
Authors: Kirsten M M Beyer, Simon Kasasa, Ronald Anguzu, Sarah Nambooze, Phoebe Mary Amulen, Courtney Jankowski, Brendah Nansereko, Yuhong Zhou, Robert Lukande, Henry Wabinga
Journal: The Lancet Global Health (2022)

The burden of cancer in Africa is growing. Although cancer outcomes are understood as the product of influences at multiple socioecological levels, population-based studies of geographical factors and cancer outcomes in Africa are scarce. The objective of this study was to identify parish-level social factors associated with cervical cancer incidence in the Kampala Cancer Registry catchment area, using a novel linkage between population-based cancer registry data and small-area census data from Uganda.Kampala Cancer Registry cervical cancer records (2008-15) were augmented to add the parish of residence at diagnosis. Parish-level population and housing profile data (2014) were obtained from the Uganda Bureau of Statistics and linked to Kampala Cancer Registry records. Stepwise forward Poisson regression modelling was used to estimate incidence ratios (IR) assessing associations between social factors and incidence. Housing tenure, infrastructure, gender equality, economic status, and employment were examined, controlling for population density. The significance level was set at α=0·05.Factors related to higher incidence included a higher girl-to-boy ratio of 6-12-year-olds not attending school (IR 1·33 [95% CI 1·15-1·54]; p<0.001), a higher percentage of 10-17-year-olds ever married (IR 1·22 [95% CI 1·06-1·40]; p=0·006) and a higher percentage of households receiving remittances (IR 1·03 [95% CI 1·00-1·06]; p=0·026). Factors associated with lower incidence included a higher percentage of household owner occupancy (IR 0·95 [95% CI 0·92-0·98]; p=0·002) and a higher percentage of households with piped water (IR 0·97 [95% CI 0·95-0·99]; p=0·009).Parish-level social factors predict cervical cancer incidence in Uganda. Communities most at risk are characterised by inequity in educational access for girls, higher prevalence of child marriage, low home ownership, inadequate infrastructure, and financial dependence. These communities would benefit from HPV vaccination and screening campaigns to prevent and control cervical cancer. Investments should be made to enhance population-based cancer surveillance and census data collection in Africa to offer new strategies and targets for cancer prevention and control.Medical College of Wisconsin Cancer Center and Medical College of Wisconsin Office of Global Health.
Abstract P1-19-02: Repurposing the FOXO4 senolytic against triple-negative breast cancer
Authors: Diana Putavet, Marjolein Baar, Tao Shi, Johannes Lehmann, Tim Leyten, Esmee Bouma, Antoine Khalil, Harm-Jan Vos, Boudewijn Burgering, Tobias Dansen, Patrick Derksen, Peter de Keizer
Journal: Cancer Research (2022)

Abstract Metastatic breast cancer is the second most common cause of cancer-related death in women. Triple Negative Breast Cancer (TNBC) has tan especially poor prognosis partly due to these tumors lacking relevant molecular targets. The most commonly mutated gene in TNBC is the tumor suppressor TP53. Mostly, p53 mutations give rise to stably expressed proteins with tumor promoting functions. Therefore, there is an urgent need for therapeutics that can target p53-mutated TNBCs. Here we show that an anti-senescence compound can target metastatic cancers. We found that, in TNBCs, mutant p53 attained a distinctive conformation that has novel oncogenic roles through binding to the transcription factor Forkhead box O (FOXO) 4 sequestered within promyelocytic leukemia (PML) foci. Since these nuclear structures are specific to senescent cells, we tested the senolytic FOXO4 peptide. In cytotoxicity experiments, we found this compound to target TNBCs specifically over other breast cancer subtypes. Most importantly, these compounds decrease metastatic burden in the most commonly-used mouse model for human breast cancer metastasis. In summary, our results demonstrate that mutant p53-driven cancers presented senescent cell-specific characteristics that makes them a great candidate for the FOXO4-directed anti-senescence therapy. We expect that creative repurposing of senolytics to translate to other types of cancer that are driven by mutant p53. Citation Format: Diana Putavet, Marjolein Baar, Tao Shi, Johannes Lehmann, Tim Leyten, Esmee Bouma, Antoine Khalil, Harm-Jan Vos, Boudewijn Burgering, Tobias Dansen, Patrick Derksen, Peter de Keizer. Repurposing the FOXO4 senolytic against triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-02.
Abstract ES9-2: Special indications where local therapy should be considered
Authors: A Lucci
Journal: Cancer Research (2022)

Abstract Clarity for the clinical issue of which patients with metastatic breast cancer should undergo local/regional therapy (LRT) was provided by the recent presentation of the prospective randomized ECOG-ACRIN 2108 trial data. This study, which randomized Stage IV breast cancer patients (initially treated with optimal systemic therapy for 4-8 months) to early local therapy or to continued systemic therapy alone, failed to demonstrate an improvement in overall survival for patients who had early local therapy compared to continued systemic therapy alone. However, there are some special indications that fall outside of this trial, and which remain areas of controversy. For instance, the subset of patients with inflammatory breast cancer (IBC) were not included in the ECOG trial, and therefore there are no prospective randomized clinical trial data available to determine if LRT improves survival in de novo stage IV IBC patients. To further confound the issue, several retrospective studies show clear survival benefit for Stage IV IBC patients who complete LRT, versus those who do not. While we all recognize that some differences could be attributed to selection bias, the differences in outcome are so striking that we believe that it warrants further discussion of the possible value of LRT in the IBC group. Furthermore, patients with IBC are more likely to be found to have Stage IV disease at presentation, complicating the discussion of whether complete trimodal therapy (neoadjuvant chemotherapy, mastectomy, and post-mastectomy radiation therapy) should still be considered at initial treatment planning, or whether LRT should be omitted altogether. Finally, due to the skin involvement and rapid progression inherent to IBC, these patients often require LRT for palliation of advanced disease (to control fungating tumors, brachial plexus involvement, etc.), so palliative surgery plays an important role in the management of the patient with IBC. During this presentation, we plan to discuss the available data regarding optimal LRT decisions for patients with de novo Stage IV IBC. Beyond the subset of IBC patients, several studies have identified non-IBC patients with Stage IV disease who might benefit from LRT. We will also discuss subsets of Stage IV breast cancer patients, including those with HR+ tumors, those with bone-only oligometastasis, and younger age patients, where LRT has shown survival benefit, based mainly on longer follow-up data from the randomized MF07-01 trial. Our objective is to improve knowledge of the local/regional treatment recommendations of select subgroups of Stage IV patients, where the use of LRT could translate to not only improved local control, but possibly to improved survival in carefully selected patients. Citation Format: A Lucci. Special indications where local therapy should be considered [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES9-2.