tbuckley/cabot-search huggingface dataset:
Abstract PS18-16: The complete estrogen receptor antagonist OP-1250 shrinks tumors in xenograft models and has favorable preclinical pharmacokinetic attributes
Authors: Leslie Hodges-Gallagher, Richard Sun, David C Myles, Pamela M Klein, Jo Anne Zujewski, Cyrus L Harmon, Peter J Kushner
Journal: Cancer Research (2021)

Abstract Antiestrogens are widely used to treat ER+, HER2- breast cancer however these may produce estrogen-like agonist effects in a cell and gene-specific manner. Furthermore, this partial agonism has been implicated in the development of tumor resistance. In contrast, a complete ER antagonist lacks agonist activity in all tissues. Given the high risk of recurrence in ER+ patients treated with endocrine therapies, we hypothesize that drugs that completely antagonize ER-mediated signaling will have a clinical advantage in treating resistant tumors, particularly in tumors for which the ER has acquired mutations conferring estrogen-independent growth. We previously identified OP-1250 in our laboratory as a complete antagonist and degrader of wild type and mutant ERalpha in breast and uterus cells. Here we explore the pharmacokinetic properties of orally administered OP-1250 and its ability to shrink breast tumors from xenograft models expressing both wild type and mutant estrogen receptors. Orally administered OP-1250 produced high and stable levels in multiple species, suggesting that once daily dosing may be sufficient to produce excellent drug exposure in patients. OP-1250 shrank ER+ tumors in multiple patient-derived tumor xenografts in mice at daily doses of 3 mg/kg, including in tumors expressing the Y537S allele of ERalpha that confers estrogen-independent growth and tumor resistance. Furthermore, OP-1250 accumulated within tumor specimens, indicating excellent target penetration was achieved with low daily doses. These preclinical studies indicate that OP-1250 has the potential to be a best-in-class antiestrogen due to its ability to complete antagonize ER, potent efficacy in shrinking tumors, and robust drug exposure. A Phase 1/2 dose escalation and expansion study in patients with ER+, HER2- metastatic or advanced BC previously treated with an endocrine therapy will be initiated this year. Citation Format: Leslie Hodges-Gallagher, Richard Sun, David C Myles, Pamela M Klein, Jo Anne Zujewski, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 shrinks tumors in xenograft models and has favorable preclinical pharmacokinetic attributes [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 PS18-16.
SARS-CoV-2 infection and adverse events in patients with cancer receiving immune checkpoint inhibitors: an observational prospective study
Authors: Mario Mandala, Paul Lorigan, Matilde De Luca, Andrea Bianchetti, Barbara Merelli, Anna Cecilia Bettini, Lucia Bonomi, Sharon Nahm, Maria Grazia Vitale, Giorgia Negrini, Andrea Di Croce, Paolo Antonio Ascierto, Eliana Rulli, Carlo Alberto Tondini
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background In ambulatory patients with cancer with asymptomatic or pauci-symptomatic SARS-CoV-2 infection, the safety of targeted therapies (TTs), chemotherapy (CT) or immune checkpoint inhibitors (ICIs) therapy is still unknown. Material and methods From the start of the first epidemic wave of SARS-CoV-2 in Bergamo, Italy, we have prospectively screened all consecutive outpatients who presented for treatment to the Oncology Division of the Papa Giovanni XXIII Hospital, Bergamo for SARS-CoV-2 antigen expression. We identified patients treated with ICIs and compared these to patients with the same cancer subtypes treated with TTs or CT. Results Between March 5 and May 18, 293 consecutive patients (49% melanoma, 34% non-small cell lung cancer, 9% renal cell carcinoma, 8% other) were included in this study: 159 (54%), 50 (17%) and 84 (29%) received ICIs, CT or TTs, respectively. Overall 89 patients (30.0%) were SARS-CoV-2 positive. Mortality of SARS-CoV-2-positive patients was statistically significantly higher compared with SARS-CoV-2 negative patients (8/89 vs 3/204, respectively, Fisher’s exact test p=0.004). All deaths were due to COVID-19. Serious adverse events (SAEs) were more frequent in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative cases (Cochran-Mantel-Haenszel (CMH) test p=0.0008). The incidence of SAEs in SARS-CoV-2 positive compared with SARS-CoV-2 negative patients was similar in ICI and CT patients (17.3% and 3.7% for positive and negative patients in ICIs and 15.4% and 2.7% in CT, Breslow-Day test p=0.891). No COVID-19-related SAEs were observed in the TTs patients. Conclusions The incidence of SAEs was higher for SARS-CoV-2-positive patients treated with ICIs and CT, mostly in advanced disease. No SAEs were observed in patients treated with TTs. SAEs were COVID-19 related rather than treatment related. Treatment with ICIs does not appear to significantly increase risk of SAEs compared with CT. This information should be considered when determining treatment options for patients.
Abstract PS6-49: Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden
Authors: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe
Journal: Cancer Research (2021)

Abstract Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. While high tumor mutation burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. Triple-negative breast cancer (TNBC) has a higher TMB and accumulates more CTLs compared to other breast cancer subtypes. CTLs are identified by CD8 surface marker, which is encoded by CD8A gene. Granzyme B (GZMB) is a serine protease that is secreted by activated CTLs to induce apoptosis of the target cells. Chemokines, such as CXCL10 and CCL5 are key to the selective attraction of activated CTLs into tumors, as shown in multiple cancers. However, it remains unknown whether tumor infiltrating functional CTLs levels correlate with improved patient survival and are independent of TMB. In order to investigate it, we developed Functional Hotness Score (FHS) combining gene expressions of markers and attractants of activated CTL. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on gene expression levels of CTL and chemokine markers in bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: CD8, GZMB and CXCL10 combination resulted in the best prediction of the breas cancer patient prognosis. Thus, we established FHS based on the expression levels of these three genes. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the metastatic breast cancers. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival in hormone receptor (HR)-negative, especially TNBC, but not in HR-positive breast cancer. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time. Conclusions: TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robust when combined with TMB in TNBCs. Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden [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 PS6-49.
Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer
Authors: Olivia A. Maguire, Sarah E. Ackerman, Sarah K. Szwed, Aarthi V. Maganti, François Marchildon, Xiaojing Huang, Daniel J. Kramer, Adriana Rosas-Villegas, Rebecca G. Gelfer, Lauren E. Turner, Victor Ceballos, Asal Hejazi, Bozena Samborska, Janane F. Rahbani, Christien B. Dykstra, Matthew G. Annis, Ji-Dung Luo, Thomas S. Carroll, Caroline S. Jiang, Andrew J. Dannenberg, Peter M. Siegel, Sarah A. Tersey, Raghavendra G. Mirmira, Lawrence Kazak, Paul Cohen
Journal: Cell Metabolism (2021)
Abstract 2020: The Effect of Global Ischemia and Reperfusion on Long Duration of Human Ventricular Fibrillation: A Multi-Electrode Mapping Study
Authors: Stephane Masse, Adel K Hamad, Rajesh Dhopeshwarkar, Salem Al-Kaabi, John Asta, Heather Ross, Terry Yau, Vivek Rao, Elias Sevaptsidis, Kumar Nanthakumar
Journal: Circulation (2007)

Introduction: The most significant change to the latest AHA CPR guidelines is the recommendation of CPR first followed by defibrillation, for un-witnessed arrests. We tested the hypothesis that global myocardial ischemia during ventricular fibrillation (VF) decreases activation rate and short duration of reperfusion would normalize activation rates. Methods: We studied 6 Langendorff perfused human hearts which were explanted from cardiomyopathic patients who underwent transplantation. Tyrode solution was used for perfusion and flow was maintained at 0.9 to 1.1 ml/g/min. Multi-electrode mapping was performed for the entire epicardium (112 electrodes sock array) and the LV endocardium (112 electrodes balloon array). VF was induced by applying a 9-volt battery on the epicardium. As soon as the VF episode was induced, perfusion was turned off for 200 seconds mimicking global ischemia. At the end of this period the perfusion system was turned back on at a flow similar to baseline for an additional 140 seconds, mimicking a state of reperfusion. The hearts were then defibrillated and this protocol was repeated twice after a rest period of 5 minutes. For the analysis, 20 s electrograms located on the LV freewall (both endo and epi) were recorded at t = 0, 90, 180, 260 and 320s, for a total of 11520 electrograms. Local Activation Rates (LAR) for each electrogram was determined as the dominant frequency (DF) corresponding to the highest value in the power spectrum between 1.5 and 8 Hz. Results: Activation rate decreased from 4.962±0.020 Hz to 3.704±0.022 Hz (p&lt;0.0001) during the 200 seconds of global ischemia. During the 140 seconds of reperfusion the activation rate increased to 4.882±0.024 Hz (p&lt;0.0001). This value was comparable to what was measured at the onset of VF (p = 0.011). These changes of rates were similar for both endocardium and epicardium data (p = 0.0236). Conclusions: During long episodes of human VF, global myocardial ischemia leads to slowing of activation rate on the epicardium and endocardium. Two minutes of re-perfusion leads to reversal of this effect. These findings may support the recent change in CPR guidelines.
Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules
Authors: Kamini Singh, Jianan Lin, Nicolas Lecomte, Prathibha Mohan, Askan Gokce, Viraj R. Sanghvi, Man Jiang, Olivera Grbovic-Huezo, Antonija Burčul, Stefan G. Stark, Paul B. Romesser, Qing Chang, Jerry P. Melchor, Rachel K. Beyer, Mark Duggan, Yoshiyuki Fukase, Guangli Yang, Ouathek Ouerfelli, Agnes Viale, Elisa de Stanchina, Andrew W. Stamford, Peter T. Meinke, Gunnar Rätsch, Steven D. Leach, Zhengqing Ouyang, Hans-Guido Wendel
Journal: Cancer Research (2021)

Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5' untranslated regions, including those with multiple G-quadruplex elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC, including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC. SIGNIFICANCE: These findings document the coordinate, eIF4A-dependent translation of RAS-related oncogenic signaling molecules and demonstrate therapeutic efficacy of eIF4A blockade in pancreatic adenocarcinoma.
Acute-on-chronic liver failure: a global disease
Authors: Martin Schulz, Jonel Trebicka
Journal: Gut (2021)

Acute-on-chronic liver failure (ACLF) is a frequent complication in hospitalised patients with liver cirrhosis. A large body of data has been published in recent years, demonstrating that acute decompensation constitutes a dramatic turning point in the course of cirrhosis, with development of ACLF being the most severe form of acute decompensation (AD).1 Within the last decades, heterogeneous definitions of ACLF have been proposed in different regions of the world, that is, the European European Association for the Study of the Liver - Chronic Liver Failure (EASL-CLIF) definition, the NASCELD definition in North American and the East Asian APASL criteria. Due to those, epidemiological data on ACLF are heterogenous and not easy to compare.

In Gut , Mezzano and colleagues have undertaken huge efforts to homogenise and compare the existing evidence.2 They present an extensive systematic review and meta-analysis on the burden of ACLF worldwide (figure 1A), which constitutes the largest epidemiological study on this subject to date.3 The authors were able to identify 30 prospective and retrospective cohort studies from around the world, which include 43 206 ACLF patients and 140 835 patients without ACLF. Strengths of this study are its scale and the robustness of data, which highlight the global significance of ACLF for patients and …
The time of onset of intradialytic hypotension during a hemodialysis session associates with clinical parameters and mortality
Authors: David F. Keane, Jochen G. Raimann, Hanjie Zhang, Joanna Willetts, Stephan Thijssen, Peter Kotanko
Journal: Kidney International (2021)

Intradialytic hypotension (IDH) is a common complication of hemodialysis, but there is no data about the time of onset during treatment. Here we describe the incidence of IDH throughout hemodialysis and associations of time of hypotension with clinical parameters and survival by analyzing data from 21 dialysis clinics in the United States to include 785682 treatments from 4348 patients. IDH was defined as a systolic blood pressure of 90 mmHg or under while IDH incidence was calculated in 30-minute intervals throughout the hemodialysis session. Associations of time of IDH with clinical and treatment parameters were explored using logistic regression and with survival using Cox-regression. Sensitivity analysis considered further IDH definitions. IDH occurred in 12% of sessions at a median time interval of 120-149 minutes. There was no notable change in IDH incidence across hemodialysis intervals (range: 2.6-3.2 episodes per 100 session-intervals). Relative blood volume and ultrafiltration volume did not notably associate with IDH in the first 90 minutes but did thereafter. Associations between central venous but not arterial oxygen saturation and IDH were present throughout hemodialysis. Patients prone to IDH early as compared to late in a session had worse survival. Sensitivity analyses suggested IDH definition affects time of onset but other analyses were comparable. Thus, our study highlights the incidence of IDH during the early part of hemodialysis which, when compared to later episodes, associates with clinical parameters and mortality.
Comparison of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot
Authors: Bryan H. Goldstein, Christopher J. Petit, Athar M. Qureshi, Courtney E. McCracken, Michael S. Kelleman, George T. Nicholson, Mark A. Law, Jeffery J. Meadows, Jeffrey D. Zampi, Shabana Shahanavaz, Christopher E. Mascio, Paul J. Chai, Jennifer C. Romano, Sarosh P. Batlivala, Shiraz A. Maskatia, Ivor B. Asztalos, Alicia M. Kamsheh, Steven J. Healan, Justin D. Smith, R. Allen Ligon, Joelle A. Pettus, Sarina Juma, James E.B. Raulston, Krissie M. Hock, Amy L. Pajk, Lindsay F. Eilers, Hala Q. Khan, Taylor C. Merritt, Matthew Canter, Stephan Juergensen, Fatuma-Ayaan Rinderknecht, Holly Bauser-Heaton, Andrew C. Glatz
Journal: Journal of the American College of Cardiology (2021)
The Transcriptional and Splicing Changes Caused by Hybridization Can Be Globally Recovered by Genome Doubling during Allopolyploidization
Authors: Jinxia Qin, Ruirui Mo, Hongxia Li, Zhongfu Ni, Qixin Sun, Zhenshan Liu
Journal: Molecular Biology and Evolution (2021)

Abstract Polyploidization is a major driving force in plant evolution. Allopolyploidization, involving hybridization and genome doubling, can cause extensive transcriptome reprogramming which confers allopolyploids higher evolutionary potential than their diploid progenitors. To date, little is known about the interplay between hybridization and genome doubling in transcriptome reprogramming. Here, we performed genome-wide analyses of transcriptome reprogramming during allopolyploidization in wheat and brassica lineages. Our results indicated that hybridization-induced transcriptional and splicing changes of genes can be largely recovered to parental levels by genome doubling in allopolyploids. As transcriptome reprogramming is an important contributor to heterosis, our finding updates a longstanding theory that heterosis in interspecific hybrids can be permanently fixed through genome doubling. Our results also indicated that much of the transcriptome reprogramming in interspecific hybrids was not caused by the merging of two parental genomes, providing novel insights into the mechanisms underlying both heterosis and hybrid speciation.
Correspondence on ‘Blood–brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment’
Authors: Omer Nuri Pamuk, Sarfaraz Hasni
Journal: Annals of the Rheumatic Diseases (2021)

We read the article by Kamintsky et al 1 with great interest. The study used dynamic contrast-enhanced MRI to calculate cross Blood–brain barrier (BBB) leakage rates in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). This article reported that patients with SLE had higher BBB leakage compared with controls. Almost a quarter of patients with SLE showed extensive BBB leakage and this SLE group had smaller cerebral grey matter volumes and impaired global cognitive function. The study provided objective evidence of impaired BBB in NPSLE. However, the exact mechanisms resulting in BBB leakage in NPSLE remain elusive. The authors have suggested a role of antiribosomal P and anti-NR2 antibodies and complement activation products as possible contributing factors to BBB leakage. …
Positional Central Sleep Apnea in a Child with Cervical Instability
Authors: Weston T. Powell, Erin W. MacKintosh, Lourdes Del Rosso, Maida L. Chen
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Positional Central Sleep Apnea in a Child with Cervical Instability." American Journal of Respiratory and Critical Care Medicine, 203(11), pp. e35–e36
Re: Dong K, Shen M, Ju G, et al. Off-clamp Retroperitoneoscopic Tumour Evacuation for Sporadic Renal Angiomyolipomas with High RENAL Nephrometry Scores: A Novel Surgical Technique and Its Outcomes. Eur Urol 2021;79:283-289
Authors: Jiangyi Wang, Wenfeng Li, Bin Xu
Journal: European Urology (2021)
kLDM: Inferring Multiple Metagenomic Association Networks Based on the Variation of Environmental Factors
Authors: Yuqing Yang, Xin Wang, Kaikun Xie, Congmin Zhu, Ning Chen, Ting Chen
Journal: Genomics Proteomics & Bioinformatics (2021)

Identification of significant biological relationships or patterns is central to many metagenomic studies. Methods that estimate association networks have been proposed for this purpose; however, they assume that associations are static, neglecting the fact that relationships in a microbial ecosystem may vary with changes in environmental factors (EFs), which can result in inaccurate estimations. Therefore, in this study, we propose a computational model, called the k-Lognormal-Dirichlet-Multinomial (kLDM) model, which estimates multiple association networks that correspond to specific environmental conditions, and simultaneously infers microbe-microbe and EF-microbe associations for each network. The effectiveness of the kLDM model was demonstrated on synthetic data, a colorectal cancer (CRC) dataset, the Tara Oceans dataset, and the American Gut Project dataset. The results revealed that the widely-used Spearman's rank correlation coefficient method performed much worse than the other methods, indicating the importance of separating samples by environmental conditions. Cancer fecal samples were then compared with cancer-free samples, and the estimation achieved by kLDM exhibited fewer associations among microbes but stronger associations between specific bacteria, especially five CRC-associated operational taxonomic units, indicating gut microbe translocation in cancer patients. Some EF-dependent associations were then found within a marine eukaryotic community. Finally, the gut microbial heterogeneity of inflammatory bowel disease patients was detected. These results demonstrate that kLDM can elucidate the complex associations within microbial ecosystems. The kLDM program, R, and Python scripts, together with all experimental datasets, are accessible at https://github.com/tinglab/kLDM.git.