tbuckley/cabot-search huggingface dataset:
Pilot study of anti-prostate-specific membrane antigen (PSMA) antibody J591 for men with metastatic castration-resistant prostate cancer (mCRPC) and unfavorable circulating tumor cell (CTC) count.
Authors: Justin M Lebenthal, Michael Sun, Jones T. Nauseef, Muhammad Junaid Niaz, Dunya Imad, Paul J. Christos, Escarleth Fernandez, Sharon Singh, Tessa A Chamberlain, Joseph Osborne, John Babich, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2021)

120 Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was observed to have CTC count decline following imaging with 111 In-J591, so a prospective study was launched to test the hypothesis that “naked” J591 leads to CTC count decline. Methods: In a Simon 2-stage dose de-escalation study, men with progressive mCRPC and unfavorable CTC count (CellSearch &gt; 4) received a single dose of J591. Initial dose cohort 300 mg with de-escalation to 20 mg. CTC count was re-assessed 4, 8, and 12 weeks following therapy along with PSA and standard imaging. An optional PSMA PET was included prior to treatment. The primary endpoint was proportion of subjects with conversion to favorable CTC count ( &lt; 5 CTCs/7.5 mL blood) and/or &gt; 30% decline from baseline within 12 weeks post-treatment. Results: 10 men were enrolled, 9 of whom were evaluable (1 died of progressive mCRPC prior to post-treatment CTC count). Median age was 71.5 years (range 60-81), 78% had prior chemo, ECOG PS 1 in 45% and 2 in 55%. 7 of 9 (78%) evaluable subjects were Halabi CALGB prognostic poor risk category and 2 (22%) intermediate. 6 of 9 had pre-treatment PSMA PET/CT (three 89 Zr-J591 and three 68 Ga-PSMA11). Though not required, all scans showed &gt; 1 lesion with SUVmax &gt; liver SUV (range 9.12-70.15). 2 of 6 in the 300 mg cohort had CTC count decline; 1 of 6 converted to favorable count (9 to 0 with decrease of 35 to 12 in other). 3 were treated with 20 mg; 1 had CTC count decline of 316 to 112, but 0 converted to favorable count. Across both cohorts, 3 of 9 had a CTC count decline at any point in time, ranging from 65-100% decline. With the pre-specified 2-stage design, enrollment was halted for futility based upon the primary endpoint of 12-week CTC count. PSA values post-treatment increased in 8 (89%) patients and remained unchanged in 1 (11%) patient. Conclusions: Single-agent anti-PSMA antibody J591 may lead to decline in CTC count, though the study did not meet its primary endpoint. A combination or maintenance approach might be preferable and is worthy of exploration.
BP in Young Adults with CKD and Associations with Cardiovascular Events and Decline in Kidney Function
Authors: Alexander J. Kula, David K. Prince, Joseph T. Flynn, Nisha Bansal
Journal: Journal of the American Society of Nephrology (2021)

BP is an important modifiable risk factor for cardiovascular events and CKD progression in middle-aged or older adults with CKD. However, studies describing the relationship between BP with outcomes in young adults with CKD are limited.
Association between 5-aminosalicylates in patients with IBD and risk of severe COVID-19: an artefactual result of research methodology?
Authors: Mohamed Attauabi, Jakob Seidelin, Johan Burisch
Journal: Gut (2021)

We have read the paper by Ungaro et al with great interest, in which the authors present an assessment of the association between IBD-related medications and the disease course of COVID-19 based on the Surveillance Epidemiology of Coronavirus Under Research Exclusion for IBD (SECURE-IBD) registry.1 Based on data from 1439 patients from this ongoing multinational registry, the authors confirm their previous suggestion that 5-aminosalicylates and/or sulfasalazine (collectively 5-ASA) might be associated with severe outcomes of COVID-19.2 The authors found that 5-ASA was significantly and independently associated with severe COVID-19 in comparison with patients not receiving 5-ASA and patients receiving monotherapy with tumour necrosis factor antagonists. However, no association was found when comparing with patients not receiving any medication and no dose–response relationship of 5-ASA was observed.

The authors are to be applauded for establishing this innovative registry enabling updated evidence-based decision-making for IBD clinicians. However, as the authors …
Association between sites of metastases (mets) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).
Authors: Dimitrios Makrakis, Leonidas Nikolaos Diamantopoulos, Vadim S Koshkin, Ajjai Shivaram Alva, Mehmet Asim Bilen, Tyler Francis Stewart, Victor Sacristan Santos, Jayanshu Jain, Rafael Morales-Barrera, Michael E. Devitt, Lucia Carril-Ajuria, Ariel Ann Nelson, Alexander Sankin, Roubini Zakopoulou, David James Pinato, Ana Fröbe, Monika Joshi, Guru Sonpavde, Petros Grivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2021)

445 Background: Different metastatic sites have variable prognostic implications in aUC. However, details on response and outcomes with ICI for particular mets is still unknown. We hypothesized that bone and liver mets would have poor response and outcomes with ICIs. Methods: We performed a retrospective cohort study in patients (pts) with aUC who received ICI. We compared overall response rate (ORR) and overall survival (OS) between pts with different mets at ICI initiation. We developed 4 different models: 1) lymph node (LN) only vs other; 2) visceral mets (bone, lung, liver) vs other; 3) bone + liver mets vs bone without liver vs liver without bone vs neither and 4) 6 factor model: a. LN +/- soft tissue/locoregional recurrence b. lung +/- (a) c. bone +/- (b) d. liver +/- (c) e. central nervous system (CNS) +/- (d) and f. other. ORR and OS were compared among groups using multivariable (adjusting for ECOG PS and hemoglobin&lt;10g/dl) logistic regression and cox regression, respectively. Results: We identified 984 pts (24 institutions); 703 and 696 were included in OS and ORR analyses, respectively. Median age at ICI start was 71 (range 32-93), 77% white race, 74% men, 67% ever smokers, 72% pure UC, 18% upper tract UC, 55% extirpative surgery. Prevalence of LN, lung, bone and liver mets at ICI start was 74%, 32%, 27% and 21%, respectively. LN-only mets had significantly higher ORR (44% vs 22%, OR 2.6, p&lt;0.05) and longer mOS (22 vs 8 months, HR 0.5, p&lt;0.05) vs other mets. Visceral mets had significantly lower ORR (21% vs 35%, OR 0.5, p&lt;0.05) and shorter mOS (7 vs 17 months, HR 1.8, p&lt;0.05) vs non-visceral mets. Pts with bone and liver mets had significantly lower ORR and shorter OS vs those with bone or liver mets, which both had significantly lower ORR and shorter OS vs those with neither and with LN +/- local recurrence (Table). Conclusions: In the context of ICI treatment, bone, liver, lung or CNS mets were associated with lower ORR and/or shorter OS, and bone and liver mets were particularly associated with low ORR and short OS. LN-only mets were associated with higher ORR and longer OS. Further work is needed to interrogate site-specific tumor-host immune interactions and identify biomarkers. Research Sponsor: None[Table: see text]
12P DNMT1/3-targeting microRNAs are over-expressed in the exosomes of estrogen-resistant breast cancer cells
Authors: D.V. Sorokin, O.E. Andreeva, E.I. Mikhaevich, Y. Shchegolev, V. Sigin, V.V. Strelnikov, A. Tanas, A.M. Scherbakov, M. Krasil’nikov
Journal: Annals of Oncology (2021)
Bacterial Mucosal Immunotherapy with MV130 Prevents Recurrent Wheezing in Children: A Randomized, Double-Blind, Placebo-controlled Clinical Trial
Authors: Antonio Nieto, Angel Mazón, María Nieto, Rafael Calderón, Susana Calaforra, Blanca Selva, Sonia Uixera, Maria José Palao, Paola Brandi, Laura Conejero, Paula Saz-Leal, Cristina Fernández-Pérez, David Sancho, José Luis Subiza, Miguel Casanovas
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Recurrent wheezing in children represents a severe public health concern. Wheezing attacks (WA), mainly associated with viral infections, lack effective preventive therapies.
Multi-omics prognosis predictive model of metastatic urothelial carcinoma (mUCs) with immunotherapy.
Authors: Ning He, Yiqun Zhang, Yadong Yang, Jianfei Wang
Journal: Journal of Clinical Oncology (2021)

482 Background: A fraction of mUCs patients can occur robust and durable responses in metastatic urothelial cancer patients treated with anti-PD-L1 agent (atezolizumab), and prognosis of immunotherapy exhibited a lack of attention. We aim to develop an effective prognosis for mUCs patients’ immunotherapy management. Methods: Public omics and clinical data of patients were collected from R package “IMvigor210CoreBiologies” (348 samples with RNA sequencing data, and 293 samples with DNA sequencing data). Immune cell infiltrations in the tumor microenvironment were quantified by single sample Gene Set Enrichment Analysis (ssGSEA). Prognosis model were trained by elastic net Cox proportional hazards algorithm, 10-fold Cross Validation were used for avoiding over fitting. Statistical analysis, survival analysis and data visualization were all carried out using the R. Results:Based on the whole transcriptome, whole exome sequencing, data were processed into five class parameters (including immunohistochemical, gene mutation, gene expression, signature score and molecular subtyping). With regularized Cox regression analysis, 17 genes ( CXCL9, GJB2, THBD, SEPT3, PLTP, LDLR, PPM1H, ACVR1C, MT1G, MT1L, ANXA2, LOC102725117, PCDHGB7, MCF2L2, APOL6, ITGAV, PCDH11X) were selected for evaluating mRNA expression level risk score, 11 immune cells (TIS, TGF β , Activated CD8+ T cell, Central memory CD4+ T cell, Central memory CD8+ T cell, Effector memory CD4+ T cell, Gamma delta T cell, Memory B cell, Eosinophil, Immature dendritic cell, Monocyte neutrophil) were selected for evaluating pathway level risk score. Then we combined mRNA risk score, signature risk score, gene mutations, PD-L1 IHC, TMB and other clinical parameters for further dimension reduction. Finally, PD-L1 in tumor-infiltrating immune cells (ICs) (HR = 0.75, 95% CI 0.64-0.89, p &lt; 1e-03), mRNA risk score (HR = 3.06, 95% CI 2.42-3.86, p &lt; 1e-06) and TMB (HR = 0.75, 95% CI 0.64-0.89, p &lt; 1e-03) were selected for Cox-model. Samples were divided into groups were by median of risk score, and there were significant difference of overall survival between high-risk and low-risk group, in training dataset (p &lt; 1e-04, AUC ( t = 6m/12m/18m ) = 0.69/0.79/0.80) and validation dataset (p &lt; 1e-04, AUC ( t = 6m/12m/18m ) = 0.77/0.82/0.85). In addition, high risk group was less response to PD-L1 immunotherapy than low risk group in our research (χ 2 test, p &lt; 2.23e-06). Conclusions: Wefirstlyconstructed a multi-omics prognosis prediction model for mUCs with immunotherapy, which may be related to different prognosis and immunotherapy response. This result may help further understanding the anti-immunotherapy of mUCs patient’s management.
Refining the Molecular Framework for Pancreatic Cancer with Single-cell and Spatial Technologies
Authors: Jimmy A. Guo, Hannah I. Hoffman, Colin D. Weekes, Lei Zheng, David T. Ting, William L. Hwang
Journal: Clinical Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy in urgent need of a molecular framework for guiding therapeutic strategies. Bulk transcriptomic efforts over the past decade have yielded two broad consensus subtypes: classical pancreatic/epithelial versus basal-like/squamous/quasi-mesenchymal. Although this binary classification enables prognostic stratification, it does not currently inform the administration of treatments uniquely sensitive to either subtype. Furthermore, bulk mRNA studies are challenged by distinguishing contributions from the neoplastic compartment versus other cell types in the microenvironment, which is accentuated in PDAC given that neoplastic cellularity can be low. The application of single-cell transcriptomics to pancreatic tumors has generally lagged behind other cancer types due in part to the difficulty of extracting high-quality RNA from enzymatically degradative tissue, but emerging studies have and will continue to shed light on intratumoral heterogeneity, malignant–stromal interactions, and subtle transcriptional programs previously obscured at the bulk level. In conjunction with insights provided by single-cell/nucleus dissociative techniques, spatially resolved technologies should also facilitate the contextualization of gene programs and inferred cell–cell interactions within the tumor architecture. Finally, given that patients often receive neoadjuvant chemotherapy and/or chemoradiotherapy even in resectable disease, deciphering the gene programs enriched in or induced by cytotoxic therapy will be crucial for developing insights into complementary treatments aimed at eradicating residual cancer cells. Taken together, single-cell and spatial technologies provide an unprecedented opportunity to refine the foundations laid by prior bulk molecular studies and significantly augment precision oncology efforts in pancreatic cancer.
Invasive Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Scientific Statement From the American Heart Association
Authors: Timothy D. Henry, Matthew I. Tomey, Jacqueline E. Tamis-Holland, Holger Thiele, Sunil V. Rao, Venu Menon, Deborah G. Klein, Yoshifumi Naka, Ileana L. Piña, Navin K. Kapur, George D. Dangas
Journal: Circulation (2021)

Cardiogenic shock (CS) remains the most common cause of mortality in patients with acute myocardial infarction. The SHOCK trial (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) demonstrated a survival benefit with early revascularization in patients with CS complicating acute myocardial infarction (AMICS) 20 years ago. After an initial improvement in mortality related to revascularization, mortality rates have plateaued. A recent Society of Coronary Angiography and Interventions classification scheme was developed to address the wide range of CS presentations. In addition, a recent scientific statement from the American Heart Association recommended the development of CS centers using standardized protocols for diagnosis and management of CS, including mechanical circulatory support devices (MCS). A number of CS programs have implemented various protocols for treating patients with AMICS, including the use of MCS, and have published promising results using such protocols. Despite this, practice patterns in the cardiac catheterization laboratory vary across health systems, and there are inconsistencies in the use or timing of MCS for AMICS. Furthermore, mortality benefit from MCS devices in AMICS has yet to be established in randomized clinical trials. In this article, we outline the best practices for the contemporary interventional management of AMICS, including coronary revascularization, the use of MCS, and special considerations such as the treatment of patients with AMICS with cardiac arrest.
Human Colonization with Extended-Spectrum Beta-Lactamase-Producing <i>E. coli</i> in Relation to Animal and Environmental Exposures in Bangladesh: An Observational One Health Study
Authors: Emily K. Rousham, Muhammad Asaduzzaman, T.I.M. Amin Uddin Mozmader, Mohammed Badrul Amin, Mahdia Rahman, Muhammed Iqbal Hossain, Md. Rayhanul Islam, Zahid Hayat Mahmud, Leanne Unicomb, Mohammad Aminul Islam
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Human exposure to intensively farmed livestock is a potential risk for transmission of antibiotic-resistant bacteria (ARB) but few studies have assessed the relative role of animal vs. environmental sources of ARB in low-resource community settings. OBJECTIVES:We conducted an observational study to compare ARB colonization and antibiotic-resistant gene prevalence and abundance in humans with high or low exposure to poultry in rural households, commercial poultry farms, and urban markets in Bangladesh.METHODS: Extended-spectrum b-lactamase (ESBL)-producing and carbapenem-resistant E. coli were quantified in feces from adults with high or low poultry exposure (n = 100, respectively), poultry (n = 200), drinking water (n = 120), and wastewater (n = 120) from 40 rural households, 40 poultry farms, and 40 urban markets.RESULTS: ESBL-producing E. coli (ESBL-EC) prevalence was 67.5% (95% CI: 61.0, 74.0) in samples from adults, 68.0% (95% CI: 61.5, 74.5) in samples from poultry, and 92.5% (95% CI: 87.7, 97.3) in wastewater samples.Carbapenem-resistant E. coli prevalence was high in market wastewaters [30% (95% CI: 15.0, 45.0)] but low in humans (1%) and poultry (1%).Human, poultry, and wastewater isolates shared common resistance genes: bla CTX-M-1 , qnr, and bla TEM .Human colonization was not significantly associated with exposure to poultry or setting (rural, farm, or market).Ninety-five percent of commercial poultry farms routinely administered antibiotics.Susceptibility tests were significantly different in household vs. farm and market poultry isolates for four of seven antibiotic classes.In human isolates, there were no differences except aminoglycoside resistance (16.4% high vs. 4.4% low exposure, p = 0:02).Urban market wastewaters and poultry samples had significantly higher concentrations of ESBL-EC (p < 0:001) and bla CTX-M-1 (p < 0:001) compared with samples from farms and rural households.DISCUSSION: ESBL-EC colonization was high in humans but not significantly associated with exposure to poultry.Bidirectional transmission of antibiotic resistance is likely between humans, poultry, and the environment in these community settings, underlining the importance of One Health mitigation strategies.
Patients with cancer appear more vulnerable to SARS-COV-2: A multi-center study during the COVID-19 outbreak
Authors: Chai, Li, Mucci, Lorelei Ann, Santillana, Mauricio, Cai, Hong-Bing
Journal: Cancer Research (2020)

Background: The novel COVID-19 outbreak, caused by the SARS-CoV-2 virus and originally detected in December 2019 in Wuhan, China, has affected more than 140 cou
HPV-16 positive clinically advanced squamous cell carcinoma of the urinary bladder (mBSCC): A comprehensive genomic profiling (CGP) study.
Authors: Joseph M Jacob, Philippe E. Spiess, Gennady Bratslavsky, Andrea Necchi, Petros Grivas, Natalie Danziger, Douglas I. Lin, Richard Huang, Douglas A Mata, Brennan James Decker, Ethan Sokol, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2021)

481 Background: mBSCC is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of mBSCC based on the association with HPV-16 to determine if differences would be observed between the positive and negative groups. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 mBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining set at 1-49% and high staining at ≥50% expression. Results: Overall, 11 (6.4%) of the mBSCC were found to harbor HPV-16 sequences (Table). HPV-16+ status was identified slightly more often in women (NS) and in younger patients (P = .04); 2 female patients with mBSCC had prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV-16+ mBSCC had fewer GA/tumor (P &lt; .0001), and fewer inactivating GA in CDKN2A (P &lt; .0001), CDKN2B (P = .05), TERT promoter (P = .0004) and TP53 (P &lt; .0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV-16+ and HPV-16- mBSCC groups. MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. MSI and TMB were also similar in the 2 groups. The 3 HPV-16+ mBSCC cases showed high positive PD-L1 IHC staining. Conclusions: HPV-16+ mBSCC tends to occur more often in women and younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV-16+ mBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation. [Table: see text]
Abstract 11877: Lipophilic, but Not Hydrophilic, Beta-blockers and Angiotensin Receptor Blockers Are Effective Treatments for Type 2 Pulmonary Hypertension
Authors: Mathew J Platt, Jason S Huber, Andrew J Foster, Jade P Marrow, Renee Kinden, Shara Birnbaum, Jonathan D Mofford, Connor J Bochek, James W Rush, Sohrab Lutchmedial, Keith R Brunt, Jeremy A Simpson
Journal: Circulation (2019)

Background: Heart Failure (HF) is a global epidemic and a leading cause of mortality in the developed world. HF patients often evolve comorbidities that further reduce quality of life and life expe...
Abstract LT017: ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology
Authors: Katarzyna A. Rejniak, Sharan Poonja, Shreya Mathur, Jessica Kingsley, Marilyn Bui
Journal: Cancer Research (2021)

Abstract Progression from a ductal carcinoma in situ (DCIS) to an invasive tumor is a major step initiating a devastating and often lethal metastatic cascade. One sentinel event that initiate this process is the development of ductal microinvasions, i.e., small cohorts of tumor cells that breach the basement membrane surrounding the duct and migrate through the extracellular matrix (ECM) leading to irreversible changes in tumor and stromal architecture. We used a combination of advanced image analysis techniques applied to patients’ histology data to extract features which identify specific properties of individual tumor cells inside the duct and on the invasive front. By integrating these histology-based data with a hybrid agent-based mathematical model, we investigated the biomechanical interactions between the cells and the ECM fiber architecture, and microenvironmental physical and metabolic features that define tumor niche prone to microinvasions. The identified physical properties of the matrix elucidate conditions that can facilitate or prevent the progression of such microinvasions. The presented method provides also a tool for quantifying morphological and immunohistochemical properties of individual cells within the mammary ducts and ductal microinvasion, as well as for testing biomechanical hypotheses of tumor cell-tumor matrix interactions. These findings can be compared to the patient histology samples and help define criteria for identification of changes in tumor architecture and future development of new diagnostic methods. Citation Format: Katarzyna A. Rejniak, Sharan Poonja, Shreya Mathur, Jessica Kingsley, Marilyn Bui. ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT017.