tbuckley/cabot-search huggingface dataset:
Analysis of recurrently protected genomic regions in cell-free DNA found in urine
Authors: Havell Markus, Jun Zhao, Tania Contente-Cuomo, Michelle D. Stephens, Elizabeth Raupach, Ahuva Odenheimer-Bergman, Sydney Connor, Bradon R. McDonald, Bethine Moore, Elizabeth Hutchins, Marissa McGilvrey, Michelina C. de la Maza, Kendall Van Keuren-Jensen, Patrick Pirrotte, Ajay Goel, Carlos Becerra, Daniel D. Von Hoff, Scott A. Celinski, Pooja Hingorani, Muhammed Murtaza
Journal: Science Translational Medicine (2021)

Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented. Whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we characterized fragmentation patterns in urine cfDNA using whole-genome sequencing. Size distribution of urine cfDNA fragments showed multiple strong peaks between 40 and 120 base pairs (bp) with a modal size of 81- and sharp 10-bp periodicity, suggesting transient protection from complete degradation. These properties were robust to preanalytical perturbations, such as at-home collection and delay in processing. Genome-wide sequencing coverage of urine cfDNA fragments revealed recurrently protected regions (RPRs) conserved across individuals, with partial overlap with nucleosome positioning maps inferred from plasma cfDNA. The ends of cfDNA fragments clustered upstream and downstream of RPRs, and nucleotide frequencies of fragment ends indicated enzymatic digestion of urine cfDNA. Compared to plasma, fragmentation patterns in urine cfDNA showed greater correlation with gene expression and chromatin accessibility in epithelial cells of the urinary tract. We determined that tumor-derived urine cfDNA exhibits a higher frequency of aberrant fragments that end within RPRs. By comparing the fraction of aberrant fragments and nucleotide frequencies of fragment ends, we identified urine samples from cancer patients with an area under the curve of 0.89. Our results revealed nonrandom genomic positioning of urine cfDNA fragments and suggested that analysis of fragmentation patterns across recurrently protected genomic loci may serve as a cancer diagnostic.
Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin’s lymphoma
Authors: Kathryn Lurain, Ramya Ramaswami, Ralph Mangusan, Anaida Widell, Irene Ekwede, Jomy George, Richard Ambinder, Martin Cheever, James L Gulley, Priscila H Goncalves, Hao-Wei Wang, Thomas S Uldrick, Robert Yarchoan
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Non-Hodgkin’s lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control. Methods We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute. Results We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1–21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2–3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide. Conclusions Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.
Abstract 1026: Macrophage-specific Transgenic Expression of Human Macrophage Cholesterol Ester Hydrolase results in Significantly Reduced Atherosclerotic Lesions in LDLR-/- mice
Authors: Bin Zhao, Jingmei Song, Woon Chow, Shobha Ghosh
Journal: Circulation (2006)

Cholesterol ester hydrolase (CEH) catalyses the rate limiting step in free cholesterol efflux from macrophage foam cells and intracellular CEH levels negatively correlate with lipid accumulation in...
Abstract PS1-37: Reduction mammoplasty in the setting of neoadjuvant chemotherapy
Authors: Kelly Hewitt, Susan Wu, Laura Barnes, Joanna Yang, Merisa Piper
Journal: Cancer Research (2021)

Abstract Background: Oncoplastic reduction mammoplasty is an accepted method of breast conserving surgery that also allows for potentially improved symmetry and aesthetics compared to other techniques and allows for larger tissue volumes to be removed with acceptable cosmetic outcomes. Neoadjuvant systemic chemotherapy (NAC) is increasingly used for the treatment of patients with breast cancer. While there is some data that oncoplastic reduction may delay timing of adjuvant radiation, we sought to examine this in our patients, and specifically to compare complications and time to radiation in patients who received NAC to those that didn’t. Methods: A retrospective analysis was done of all patients with DCIS or invasive cancer who underwent a reduction mammoplasty and received adjuvant radiation at our single institution from 2009-2018. Patients who received NAC were compared to those that did not. Results: A total of 114 patients underwent reduction mammoplasty as part of their oncologic surgery and received adjuvant radiation at our institution. Of those, 40.4% received neoadjuvant chemotherapy and 49.1% received no neoadjuvant treatment. A total of 38 patients (33.3%) had some postoperative complication with 8.8% having a serious complication that required intervention. Adjuvant radiation started after 8 weeks in 74.6% of patients and after 12 weeks in 38.6% of patients, with the majority of these delays due to non-clinical factors. A total of 29.4% of patients had a delay due to wound healing issues. There was no association between NAC and delayed radiation due to wound healing (p=0.18). Discussion: Oncoplastic reduction mammoplasty is a safe option for breast-conserving surgery in patients who have received NAC. The receipt of NAC in itself does not delay timing of adjuvant radiation or lead to increases in delayed wound healing. We are additionally examining other factors and their possible interaction with NAC, including diabetes, smoking, BMI and breast reduction size. In those with larger tumors receiving NAC who would otherwise not be candidates for breast conserving surgery, oncoplastic reduction should be considered as an appropriate option for surgical management. Reduction also allows for wider excision which may mitigate the impact of the longer time from surgery to radiation. Citation Format: Kelly Hewitt, Susan Wu, Laura Barnes, Joanna Yang, Merisa Piper. Reduction mammoplasty in the setting of neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-37.
Pulmonary fibrosis screening: quantifying the psychological impact
Authors: Chad A Newton
Journal: Thorax (2021)

Screening programmes have transformed outcomes in a number of conditions such as diabetes, cardiovascular disease and cancer. For example, lung cancer screening has effectively reduced cancer-associated mortality1 by identifying premetastatic lesions amenable to curative or highly effective therapies. Therefore, it is natural to wonder if screening for a similarly morbid disease such as pulmonary fibrosis (PF) could yield comparable results. A decade ago, screening for PF would likely have had little impact on the natural history of these disorders. However, three recent discoveries have made PF screening potentially more consequential: (1) the identification of interstitial lung abnormalities (ILA) which are thought to be PF precursor lesions2 3; (2) the realisation that asymptomatic relatives of patients with PF represent a sizeable at-risk population that are enriched for ILAs4–6; and (3) the development of antifibrotic therapies that are effective even for individuals with preserved lung function.7 8 Thus, the stage is now set to determine if PF screening is a viable avenue for improving clinical outcomes.

In our zest to construct PF screening algorithms, we must acknowledge that such programmes may have unintended consequences. By definition, PF screening would aim to identify a potentially fatal disorder in individuals who do not yet have symptoms, a process which could cause excessive emotional or psychological …
Abstract 14150: Ectopic Wild Type Gene Transfer Successfully Corrects Vascular Smooth Muscle Phenotypes of Adipose Tissue Triglyceride Lipase Deficient Mouse
Authors: Yanhui Lin, Shunmei Chiba, Akira Suzuki, Satoshi Yamaguchi, Takaya Nakanishi, Hirofumi Matsumoto, Yoshihiko Ikeda, Hatsue Ishibashi-Ueda, Ken-ichi Hirano, Seiya Kato
Journal: Circulation (2012)

Background: Hereditary mutated adipose tissue triglyceride lipase (ATGL) causes triglyceride-deposit cardiovasculopathy (TGCV). In addition to cardiomyocyte steatosis, coronary atherosclerosis in t...
Abstract PS18-24: Impact of protein corona formation on Fn14-targeted DART nanoparticle selectivity, uptake, and cytotoxicity on TNBC cells
Authors: Christine P Carney, Anshika Kapur, Nikhil Pandey, Jimena G Dancy, Aniket S Wadajkar, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim
Journal: Cancer Research (2021)

Abstract Despite dramatic improvements in the treatment of primary breast cancers, there currently are no effective targeted therapeutics for women diagnosed with metastatic triple negative breast cancer (mTNBC), resulting in an overall survival of just ~13 months in these patients. Drug-loaded nanoparticles (NPs) offer the potential to improve the therapeutic efficacy and pharmacokinetic profile of drugs through use of passive and active targeting to metastatic tumors. However, effective and active targeting of nanodrug formulations to tumor cells is complicated by the adsorption of proteins to NP surfaces upon exposure to the systemic circulation. Termed ‘protein coronas’, this protein coat can drastically reduce the blood circulation time and targeting capability of NPs in vivo. We have developed paclitaxel (PTX)-loaded NPs that are engineered for decreased non-specific adhesivity and receptor-targeting (‘DART’) characteristics, which balance minimal recognition by circulating immune cells and low non-specific binding to tumor extracellular matrix proteins with maximal targeting to tumor tissues. These DARTs selectively bind the fibroblast growth factor-inducible 14 (Fn14) cell surface receptor, which is overexpressed in over a dozen solid cancers and their metastases, including mTNBC tumors. We recently demonstrated the enhanced therapeutic efficacy of Fn14-targeted DARTs in comparison to a non-targeted nanoformulation and Abraxane, an FDA-approved nanoformulation for mTNBC, in xenograft models of primary and intracranial TNBC. In addition, we found that these DARTs retain targeting capability and traffic to Fn14+ tumors in the presence of an endogenous protein corona in vitro and in vivo. This encouraged further investigation into the specific mechanisms of DART NP uptake in tumor cells in both the presence and absence of protein coronas using surface plasmon resonance, flow cytometry, total internal reflection fluorescence and confocal microscopy, and cytotoxicity assays. Understanding the role of protein coronas on this drug delivery platform is crucial for its clinical development and these results provide valuable new information pertaining to the optimization of NP surface properties for minimizing the impact of protein coronas and improving mTNBC tumor targeting in vivo. Citation Format: Christine P Carney, Anshika Kapur, Nikhil Pandey, Jimena G Dancy, Aniket S Wadajkar, Graeme F Woodworth, Jeffrey A Winkles, Anthony J Kim. Impact of protein corona formation on Fn14-targeted DART nanoparticle selectivity, uptake, and cytotoxicity on TNBC cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-24.
Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries
Authors: Tao Wang, Andrea Wagner, Renate Gehwolf, Wenjin Yan, Fabian S. Passini, Christine Thien, Nadja Weissenbacher, Zhen Lin, Christine Lehner, Huajian Teng, Claudia Wittner, Qiujian Zheng, Jin Dai, Ming Ni, Allan Wang, John Papadimitriou, Toby Leys, Rocky S. Tuan, Sasha Senck, Jess G. Snedeker, Herbert Tempfer, Qing Jiang, Ming H. Zheng, Andreas Traweger
Journal: Science Translational Medicine (2021)

The extracellular matrix protein SPARC modulates load sensing in tendons and is critical for tissue maturation and homeostasis.
Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells
Authors: Mohamad Assi, Younes Achouri, Axelle Loriot, Nicolas Dauguet, Hajar Dahou, Jonathan Baldan, Maxime Libert, Jean S. Fain, Carmen Guerra, Luc Bouwens, Mariano Barbacid, Frédéric P. Lemaigre, Patrick Jacquemin
Journal: Cancer Research (2021)

Abstract Pancreatic acinar cells are a cell type of origin for pancreatic cancer that become progressively less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth. This sensitivity is increased when Kras mutations are combined with pancreatitis. Molecular mechanisms underlying these observations are still largely unknown. To identify these mechanisms, we generated the first CRISPR-edited mouse models that enable detection of wild-type and mutant KRAS proteins in vivo. Analysis of these mouse models revealed that more than 75% of adult acinar cells are devoid of detectable KRAS protein. In the 25% of acinar cells expressing KRAS protein, transcriptomic analysis highlighted a slight upregulation of the RAS and MAPK pathways. However, at the protein level, only marginal pancreatic expression of essential KRAS effectors, including C-RAF, was observed. The expression of KRAS and its effectors gradually decreased after birth. The low sensitivity of adult acinar cells to Kras mutations resulted from low expression of KRAS and its effectors and the subsequent lack of activation of RAS/MAPK pathways. Pancreatitis triggered expression of KRAS and its effectors as well as subsequent activation of downstream signaling; this induction required the activity of EGFR. Finally, expression of C-RAF in adult pancreas was required for pancreatic tumorigenesis. In conclusion, our study reveals that control of the expression of KRAS and its effectors regulates the sensitivity of acinar cells to transformation by oncogenic Kras mutations. Significance: This study generates new mouse models to study regulation of KRAS during pancreatic tumorigenesis and highlights a novel mechanism through which pancreatitis sensitizes acinar cells to Kras mutations.
Cardiolipin, Mitochondria, and Neurological Disease
Authors: Micol Falabella, Hilary J. Vernon, Michael G. Hanna, Steven M. Claypool, Robert D.S. Pitceathly
Journal: Trends in Endocrinology and Metabolism (2021)

Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.
Abstract PS1-25: Axillary management after neoadjuvant chemotherapy in initially node positive early breast cancer
Authors: Serafin Morales Murillo, Ariadna Gasol Cudós, Ona Pallisé Subirats, Jordi Melé Olivé, Carles Canosa Morales, Felip Vilardell Villellas, Douglas René Sanchez Guzman, Joel Veas Rodriguez, Alvaro Rodriguez Galindo
Journal: Cancer Research (2021)

Abstract Response to neoadjuvant treatment could modify axillary management of those with node involvement at diagnosis. We investigated whether histological response correlates with node response and could avoid axillary dissection. A series of 339 patients with node positive early breast cancer who received neoadjuvant chemotherapy was analysed. We reported the axillary conversion (ypN0) rate and its association between clinical/pathological parameters. Median age was of 52 (24-89), median tumor size of 38mm; 120 (35%) patients were HER2 positive, 132 (39%) were luminal, and 87 (26%) were triple negative breast cancer. 113 (33%) patients obtained breast pathological complete response (breastpCR): 53/120 (44%) in HER2 positive, 21/132 (16%) in luminal and 39/87 (45%) in triple negative breast cancer. Axillary conversion to ypN0 rate was of 157/339 (46%): 71/120 (59%) in HER2 positive, 40/132 (30%) in luminal and 46/87 (53%) in triple negative breast cancer. It was found a 105/339 (31%) of relapse, and mean survival was of 147 months (CI 95% 134-159). Of 113 patients with breastpCR, 94 achieved axillary ypN0 (83%) (OD=12.8, p=0.000): 45/53 of breastpCR in HER2 positive (85%) (OD=8.8; p=0.069); 16/21 of breastpCR in luminal (76%) (OD=11.6; p=0.000); 33/39 (85%) of breastpCR in triple negative breast cancer (OD=14.8; p=0.002). Residual axillary involvement in breastpCR is reported in the table.Conclusion: Global axillary conversion in patients with breastpCR was of 83%; being HER2 and triple negative those with major association. BreastpCR could predict axillary conversion in triple negative breast cancer (OD=14.8; p=0.002) and the residual node involvement never was more than 3 positive nodes. These patients could avoid axillary dissection if an adequate sentinel node biopsy is performed. Axillary conversion in breastpCRGlobal (113)HER2 (53)Luminal (21)TN (39)ypN094 (83%)45 (85%)16 (76%)33 (85%)1 node8 (7%)3 (5%)1 (5%)4 (10%)2 nodes1 (0.8%)001 (2.5%)3 nodes1 (0.8%)001 (2.5%)&amp;gt;3nodes9 (7.9%)5 (10%)4 (19%)0 Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Ona Pallisé Subirats, Jordi Melé Olivé, Carles Canosa Morales, Felip Vilardell Villellas, Douglas René Sanchez Guzman, Joel Veas Rodriguez, Alvaro Rodriguez Galindo. Axillary management after neoadjuvant chemotherapy in initially node positive early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-25.
Low awareness of past SARS-CoV-2 infection in healthy plasma donors
Authors: Katja van den Hurk, Eva-Maria Merz, Femmeke J. Prinsze, Marloes L.C. Spekman, Franke A. Quee, Steven Ramondt, Ed Slot, Hans Vrielink, Elisabeth M.J. Huis in ’t Veld, Hans L. Zaaijer, Boris M. Hogema
Journal: Cell Reports Medicine (2021)

Awareness of infection with SARS-CoV-2 is crucial for the effectiveness of COVID-19 control measures. Here, we investigate awareness of infection and symptoms in relation to antibodies against SARS-CoV-2 in healthy plasma donors. We asked individuals donating plasma across the Netherlands between May 11th and 18th 2020 to report COVID-19-related symptoms, and we tested for antibodies indicative of a past infection with SARS-CoV-2. Among 3,676 with antibodies, and from questionnaire data, 239 (6.5%) are positive for SARS-CoV-2 antibodies. Of those, 48% suspect no COVID-19, despite the majority reporting symptoms; 11% of seropositive individuals report no symptoms and 27% very mild symptoms at any time during the first peak of the epidemic. Anosmia/ageusia and fever are most strongly associated with seropositivity. Almost half of seropositive individuals do not suspect SARS-CoV-2 infection. Improved recognition of COVID-19 symptoms, in particular, anosmia/ageusia and fever, is needed to reduce widespread SARS-CoV-2 transmission.
Reply to Katakwar et al.
Authors: Gontrand Lopez-Nava, Ravishankar Asokkumar
Journal: Endoscopy (2021)

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