tbuckley/cabot-search huggingface dataset:
The B7-H3–Targeting Antibody–Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models
Authors: Nathan M. Kendsersky, Jarrett Lindsay, E. Anders Kolb, Malcolm A. Smith, Beverly A. Teicher, Stephen W. Erickson, Eric J. Earley, Yael P. Mosse, Daniel Martinez, Jennifer Pogoriler, Kateryna Krytska, Khushbu Patel, David Groff, Matthew Tsang, Samson Ghilu, Yifei Wang, Steven Seaman, Yang Feng, Brad St. Croix, Richard Gorlick, Raushan Kurmasheva, Peter J. Houghton, John M. Maris
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the CD276 gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line–derived xenograft (CDX) models. Experimental Design: B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (N = 3), rhabdomyosarcoma (N = 4), Wilms tumors (N = 2), osteosarcoma (N = 5), and neuroblastoma (N = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD. Results: The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks. Conclusions: m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.
Abstract SP121: Personalized treatment for early stage HER2-positive breast cancer
Authors: A Prat
Journal: Cancer Research (2021)

Abstract In my presentation, I will review the main clinical questions to be addressed in early-stage HER2+ disease, including the latest results from clinical trials as well as biomarker studies. Overall, the objective of my presentation is to dissect how personalized treatment of HER2+ early breast cancer has evolved in the last decade, and how is becoming a reality in particular settings, such as residual disease following standard neoadjuvant anti-HER2 therapies or in stage 1 disease. Moreover, I will discuss how the field is evolving to improve personalization of therapies and/or approaches even more in the upcoming years. Citation Format: A Prat. Personalized treatment for early stage HER2-positive 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 SP121.
Biogeographic and Evolutionary Patterns of Trace Element Utilization in Marine Microbial World
Authors: Yinzhen Xu, Jiayu Cao, Liang Jiang, Yan Zhang
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Trace elements are required by all organisms, which are key components of many enzymes catalyzing important biological reactions. Many trace element-dependent proteins have been characterized; however, little is known about their occurrence in microbial communities in diverse environments, especially the global marine ecosystem. Moreover, the relationships between trace element utilization and different types of environmental stressors are unclear. In this study, we used metagenomic data from the Global Ocean Sampling expedition project to identify the biogeographic distribution of genes encoding trace element-dependent proteins (for copper, molybdenum, cobalt, nickel, and selenium) in a variety of marine and non-marine aquatic samples. More than 56,000 metalloprotein and selenoprotein genes corresponding to nearly 100 families were predicted, becoming the largest dataset of marine metalloprotein and selenoprotein genes reported to date. In addition, samples with enriched or depleted metalloprotein/selenoprotein genes were identified, suggesting an active or inactive usage of these micronutrients in various sites. Further analysis of interactions among the elements showed significant correlations between some of them, especially those between nickel and selenium/copper. Finally, investigation of the relationships between environmental conditions and metalloprotein/selenoprotein families revealed that many environmental factors might contribute to the evolution of different metalloprotein and/or selenoprotein genes in the marine microbial world. Our data provide new insights into the utilization and biological roles of these trace elements in extant marine microbes, and might also be helpful for the understanding of how these organisms have adapted to their local environments.
Target specific tight junction modulators
Authors: Joël Brunner, Sakthikumar Ragupathy, Gerrit Borchard
Journal: Advanced Drug Delivery Reviews (2021)

Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g., blood–brain barrier). In order to enhance paracellular transport of drugs and increase their bioavailability and organ deposition, active excipients modulating tight junctions have been applied. First-generation of permeation enhancers (PEs) acted by unspecific interactions, while recently developed PEs address specific physiological mechanisms. Such target specific tight junction modulators (TJMs) have the advantage of a defined specific mechanism of action. To date, merely a few of these novel active excipients has entered into clinical trials, as their lack in safety and efficiency in vivo often impedes their commercialisation. A stronger focus on the development of such active excipients would result in an economic and therapeutic improvement of current and future drugs.
Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial
Authors: Robin L. Jones, Andrew J. Wagner, Akira Kawai, Kazuo Tamura, Ashwin Shahir, Brian A. Van Tine, Javier Martín-Broto, Patrick M. Peterson, Jennifer Wright, William D. Tap
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943). Patients and Methods: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m2. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to &amp;lt;50%, or decrease from baseline value &amp;gt;10%. Results: A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m2 (range, 72.3–634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving &amp;lt;450 mg/m2, 88.5% receiving 450–&amp;lt;600 mg/m2, and 90% receiving ≥600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose &amp;lt;450 mg/m2, 82 of 159 patients (51.6%) who received 450–&amp;lt;600 mg/m2, and 50 of 89 patients (56.2%) who received ≥600 mg/m2. Grade ≥3 cardiac dysfunction occurred in 2% of patients at &amp;lt;450 mg/m2, 3% at 450–&amp;lt;600 mg/m2, and 1.1% at ≥600 mg/m2. Incidence of treatment-related cardiac AEs was low across all dose ranges. Conclusions: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (&amp;gt;450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration. See related commentary by Benjamin and Minotti, p. 3809
Herbicide Selection Promotes Antibiotic Resistance in Soil Microbiomes
Authors: Hanpeng Liao, Xi Li, Qiue Yang, Yudan Bai, Peng Cui, Chang Wen, Chen Liu, Zhi Chen, Jiahuan Tang, Jiangang Che, Zhen Yu, Stefan Geisen, Shungui Zhou, Ville-Petri Friman, Yong-Guan Zhu
Journal: Molecular Biology and Evolution (2021)

Abstract Herbicides are one of the most widely used chemicals in agriculture. While they are known to be harmful to nontarget organisms, the effects of herbicides on the composition and functioning of soil microbial communities remain unclear. Here we show that application of three widely used herbicides—glyphosate, glufosinate, and dicamba—increase the prevalence of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in soil microbiomes without clear changes in the abundance, diversity and composition of bacterial communities. Mechanistically, these results could be explained by a positive selection for more tolerant genotypes that acquired several mutations in previously well-characterized herbicide and ARGs. Moreover, herbicide exposure increased cell membrane permeability and conjugation frequency of multidrug resistance plasmids, promoting ARG movement between bacteria. A similar pattern was found in agricultural soils across 11 provinces in China, where herbicide application, and the levels of glyphosate residues in soils, were associated with increased ARG and MGE abundances relative to herbicide-free control sites. Together, our results show that herbicide application can enrich ARGs and MGEs by changing the genetic composition of soil microbiomes, potentially contributing to the global antimicrobial resistance problem in agricultural environments.
Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR—final report from AFTER-SKI
Authors: Johan Richter, Anna Lübking, Stina Söderlund, Kourosh Lotfi, Berit Markevärn, Anders Själander, Leif Stenke, Stefan Deneberg, Erik Ahlstrand, Kristina Myhr-Eriksson, Panayiotis Panayiotidis, Tobias Gedde-Dahl, Daniela Žáčková, Jiří Mayer, Ulla Olsson-Strömberg, Francois-Xavier Mahon, Susanne Saussele, Henrik Hjorth-Hansen, Perttu Koskenvesa
Journal: Leukemia (2021)
Biomimetic lipid Nanocomplexes incorporating STAT3-inhibiting peptides effectively infiltrate the lung barrier and ameliorate pulmonary fibrosis
Authors: Hyeongseop Keum, Jinjoo Kim, Dohyun Yoo, Tae Woo Kim, Changjin Seo, Dohyeon Kim, Sangyong Jon
Journal: Journal of Controlled Release (2021)
Correction to: MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents
Authors: Arnold Bolomsky, Meike Vogler, Murat Cem Köse, Caroline A. Heckman, Grégory Ehx, Heinz Ludwig, Jo Caers
Journal: Journal of Hematology & Oncology (2021)

An amendment to this paper has been published and can be accessed via the original article.
FDG PET Unveils the Course of Paraneoplastic Cerebellar Degeneration
Authors: Federico Massa, Laura Filippi, Luana Benedetti, Silvia Morbelli, Flavio Nobili
Journal: Clinical Nuclear Medicine (2021)

In paraneoplastic cerebellar degeneration (PCD), the standard diagnostic workup might be inconclusive, especially in seronegative subtypes. Brain 18F-FDG PET is an accurate supportive diagnostic tool in immune-mediated disorders, but findings in PCD are controversial. Semiquantitative analysis of 18F-FDG PET can meaningfully assist visual assessment in different neurological conditions and has been mainly applied to disclose regional hypometabolism. We describe a seronegative PCD associated with small cell lung cancer in which 18F-FDG PET semiquantitative analysis accurately disclosed the longitudinal pathological changes of brain metabolism occurring in the acute and posttreatment remission stages and paralleling clinical impairment and response to treatment.
Radiographic and High-Throughput Sequencing (HTS)-Based Response Assessment after Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Updated Results of a Phase I/II Trial
Authors: Ryan D. Cassaday, Jonathan R. Fromm, Andrew J. Cowan, Stephen D. Smith, Edward N. Libby, Mary Philip, Margaret E. Nartea, Christen N. Heye, Sandra L. Kanan, Sanaz Behnia, Ajay K. Gopal
Journal: Blood (2017)
Risk Factors for Longitudinal Resting Heart Rate and Its Associations With Cardiovascular Outcomes in the DCCT/EDIC Study
Authors: Sareh Keshavarzi, Barbara H. Braffett, Rodica Pop-Busui, Trevor J. Orchard, Elsayed Z. Soliman, Gayle M. Lorenzi, Annette Barnie, Amy B. Karger, Rose A. Gubitosi-Klug, Samuel Dagogo-Jack, Andrew D. Paterson
Journal: Diabetes Care (2021)

Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk.Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC.At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA1c, higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors.After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA1c.
A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage
Authors: Xueqing Zou, Gene Ching Chiek Koh, Arjun Scott Nanda, Andrea Degasperi, Katie Urgo, Theodoros I. Roumeliotis, Chukwuma A. Agu, Cherif Badja, Sophie Momen, Jamie Young, Tauanne Dias Amarante, Lucy Side, Glen Brice, Vanesa Perez-Alonso, Daniel Rueda, Celine Gomez, Wendy Bushell, Rebecca Harris, Jyoti S. Choudhary, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E. H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Adam Giess, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J. P. Hubbard, Kristina ibáñez, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Kay Lawson, Sarah E. A. Leigh, Ivonne U. S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Pter O’Donovan, Chris A. Odhams, Andrea Orioli, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Mina Ryten, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Samuel C. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Mélanie Tanguy, Ellen R. A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Arianna Tucci, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Josef Jiricny, William C. Skarnes, Serena Nik-Zainal
Journal: Nature Cancer (2021)
Abstract 15130: Renal Dysfunction in Fontan Patients Assessed by Ultrasonography
Authors: Eriko Shimada, Kei Inai, Tokuko Shinohara, Hisashi Sugiyama
Journal: Circulation (2018)

Background: Renal Doppler ultrasonography has recently been investigated for profiling renal hemodynamics in the setting of heart failure. Objectives: To clarify the clinical significance of measur...
An irregular ulcer in the rectum
Authors: Qiang Wang, Ji-Na Zheng, Jian-Min Xu, Yun-Shi Zhong
Journal: BMJ (2021)

A man in his 50s was referred to hospital by his general practitioner with a suspected rectal lesion after rectal examination. He had also experienced intermittent constipation without rectal pain for five years, which he had managed with self-administered simple enemas once a week for the past three years, but these were not effective at relieving the constipation. He had a medical history of intolerance to penicillin. Full details of his sexual history could not be elicited.

Digital rectal examination showed a non-tender rectal lesion of about 3 cm in diameter on the left side of the rectum; it had a smooth base, was slightly raised, and had indurated borders.

Relevant laboratory test results are shown in table 1.

View this table:

Table 1 
Relevant laboratory test results



Magnetic resonance imaging showed irregular low rectal wall thickening (about 4 cm …
Abstract 3670: A Newly Developed Novel Index for Assessing the Degree of Coronary Stenosis Calculated from Pressure Guide Wire
Authors: Takashi Masho, Takashi Kubo, Akio Kuroi, Satoshi Ueno, Takashi Tanimoto, Takashi Yamano, Yoshiki Matsuo, Hiroki Kitabata, Shigeho Takarada, Toshio Imanishi, Yoshiaki Tomobuchi, Takashi Akasaka
Journal: Circulation (2006)

[Background] Although the measurement of fractional flow reserve (FFR) with a pressure guide wire system is useful to estimate the degree of coronary artery stenosis, it is necessary to take zero b...
miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques
Authors: Milessa Silva Afonso, Monika Sharma, Martin Schlegel, Coen van Solingen, Graeme J. Koelwyn, Lianne C. Shanley, Lauren Beckett, Daniel Peled, Karishma Rahman, Chiara Giannarelli, Huilin Li, Emily J. Brown, Alireza Khodadadi-Jamayran, Edward A. Fisher, Kathryn J. Moore
Journal: Circulation Research (2021)

Rationale: MicroRNA-33 (miR-33 [post-transcriptionally in the rationale]) post-transcriptionally represses genes involved in lipid metabolism and energy homeostasis. Targeted inhibition of miR-33 increases plasma HDL (high-density lipoprotein) cholesterol and promotes atherosclerosis regression, in part, by enhancing reverse cholesterol transport and dampening plaque inflammation. However, how miR-33 reshapes the immune microenvironment of plaques remains poorly understood. Objective: To define how miR-33 inhibition alters the dynamic balance and transcriptional landscape of immune cells in atherosclerotic plaques. Methods and Results: We used single-cell RNA-sequencing of aortic CD45 + cells, combined with immunohistologic, morphometric, and flow cytometric analyses to define the changes in plaque immune cell composition, gene expression, and function following miR-33 inhibition. We report that anti–miR-33 treatment of Ldlr –/– mice with advanced atherosclerosis reduced plaque burden and altered the plaque immune cell landscape by shifting the balance of proatherosclerotic and antiatherosclerotic macrophage and T-cell subsets. By quantifying the kinetic processes that determine plaque macrophage burden, we found that anti–miR-33 reduced levels of circulating monocytes and splenic myeloid progenitors, decreased macrophage proliferation and retention, and promoted macrophage attrition by apoptosis and efferocytotic clearance. Single-cell RNA-sequencing of aortic arch plaques showed that anti–miR-33 reduced the frequency of MHCII hi (major histocompatibility complex II) inflammatory and Trem2 hi (Triggering Receptor Expressed On Myeloid Cells 2) metabolic macrophages, but not tissue-resident macrophages. Furthermore, anti–miR-33 led to derepression of distinct miR-33 target genes in the different macrophage subsets: in resident and Trem2 hi macrophages, anti–miR-33 relieved repression of miR-33 target genes involved in lipid metabolism (eg, Abca1 , Ncoa1, Ncoa2 , Crot ), whereas in MHCII hi macrophages, anti–miR-33 upregulated target genes involved in chromatin remodeling and transcriptional regulation. Anti–miR-33 also reduced the accumulation of aortic CD8+ T cells and CD4+ T-helper 1 cells, and increased levels of FoxP3+ (Forkhead Box P3) regulatory T cells in plaques, consistent with an immune-dampening effect on plaque inflammation. Conclusions: Our results provide insight into the immune mechanisms and cellular players that execute anti–miR-33’s atheroprotective actions in the plaque.
APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function
Authors: Monica Xiong, Hong Jiang, Javier Remolina Serrano, Ernesto R. Gonzales, Chao Wang, Maud Gratuze, Rosa Hoyle, Nga Bien-Ly, Adam P. Silverman, Patrick M. Sullivan, Ryan J. Watts, Jason D. Ulrich, Gregory J. Zipfel, David M. Holtzman
Journal: Science Translational Medicine (2021)

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4+/+ (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.