tbuckley/cabot-search huggingface dataset:
Abstract 1460: The design and biological characterization of PTP4A-targeted chemodegraders
Authors: Duncan J. Hart, Ettore J. Rastelli, Anna J. Mendelson, Christopher T. Letai, John Robert Cornelison, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo
Journal: Cancer Research (2021)

Abstract The protein tyrosine phosphatase 4A (PTP4A) family members, PTP4A1, PTP4A2 or PTP4A3, are overexpressed in many cancers, and this overexpression is associated with a distinct disadvantage to overall patient survival. Genetic knockdown or deletion of PTP4A diminishes cancer cell migration, survival and tumorigenesis. We previously demonstrated that the small molecule JMS-053 or KVX-053 (7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-dione) functions as a selective, allosteric, and reversible pan-PTP4A, inhibitor. KVX-053 decreased ovarian cancer cell line spheroid viability, migration and in vivo tumor growth. We now report a conjugate of KVX-053 to an adamantyl moiety in an effort to design intracellular PTP4A chemodegraders. In addition to the linker length, we also modified the functional group attachments to the KVX-053 pharmacophore and the adamantly moiety. Significantly, several of these analogs retained potent in vitroinhibition of PTP4A3 enzymatic activity (IC50=100-750 nM), suggesting they could be dual-purpose PTP4A3 inhibitors, targeting both the catalytic activity and reducing intracellular protein concentration. Some of these KVX-053 analogs, including EJR-876-35 and EJR-887-35, exhibited enhanced cytotoxicity against human ovarian cancer, triple negative breast cancer or leukemia cell lines compared to the parent chemotype, KVX-053. Human ovarian cancer cells incubated with 1 micromolar EJR-887-35 exhibited a pronounced loss of PTP4A protein within 6 hours and the loss was sustained for at least 18 hours. These results support the further investigation of chemodegraders as specific first-in-class bifunctional PTP4A inhibitors directed against human cancers. Citation Format: Duncan J. Hart, Ettore J. Rastelli, Anna J. Mendelson, Christopher T. Letai, John Robert Cornelison, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. The design and biological characterization of PTP4A-targeted chemodegraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1460.
Features of Systemic Immune Response From COVID-19 Vaccination on 18F-FDG PET/CT
Authors: Ayah Adel Nawwar, Julie Searle, Iain Douglas Lyburn
Journal: Clinical Nuclear Medicine (2021)

Abstract The rapid rollout of COVID-19 vaccination is accompanied by incidental findings on 18 F-FDG PET/CT. Most cases describe reactive axillary lymphadenopathy. A 46-year-old woman with previous history of stage 3A breast cancer underwent follow-up 18 F-FDG PET/CT, which demonstrated avid left axillary nodes and intense diffuse splenic uptake and moderate diffuse bone marrow uptake. She had been administered COVID-19 vaccination in the left deltoid 1 week earlier and required hospitalization for 24 hours due to fever. Symptoms settled with supportive treatment. One month after the PET/CT scan, she remained well. Sites of uptake were taken to relate to a systemic immune response.
Combination of mAb cG250 with natural killer cells for RCC treatment
Authors: J.C. Oosterwijk-Wakka, S. Lafferty-Van Eijk, P.M.M. Van Hauten, R.J.A. Maas, P.K.J.D. De Jonge, H. Dolstra, P.F.A. Mulders, E. Oosterwijk
Journal: European Urology (2021)
The natural history of sarcomatoid renal-cell carcinoma, a stage-by-stage analysis
Authors: K.H. Tully, S. Berg, M. Paciotti, F. Janisch, S.W. Reese, G. Lughezzani, J. Noldus, S.F. Shariat, S.L. Chang, Q-D. Trinh, M. Mossanen
Journal: European Urology (2021)
Rajendra Kapila
Authors: Sanjeet Bagcchi
Journal: The Lancet Infectious Diseases (2021)

He was diagnosed with COVID-19 on April 8, 2021, and died from the disease at an Indian hospital, at the age of 81 years.Calling him "a genuine giant in the field of infectious diseases", Rutgers University remembered his 50 years of services in taking care of thousands of patients and training a large number of medical students, fellows, and residents, at the University Hospital, New Jersey Medical School, and the Martland Hospital.In a statement, the university also remembered Kapila's contribution as a globally recognised infectious disease specialist with phenomenal knowledge and sharpness in diagnosing and treating the "most complex" diseases.
Large‐scale serum analysis identifies unique systemic biomarkers in psoriasis and hidradenitis suppurativa*
Authors: K. Navrazhina, Y. Renert‐Yuval, J.W. Frew, D. Grand, J. Gonzalez, S.C. Williams, S. Garcet, J.G. Krueger
Journal: British Journal of Dermatology (2021)

Background Hidradenitis suppurativa (HS) is now recognized as a systemic inflammatory disease, sharing molecular similarities with psoriasis. Direct comparison of the systemic inflammation in HS with psoriasis is lacking. Objectives To evaluate the serum proteome of HS and psoriasis, and to identify biomarkers associated with disease severity. Methods In this cross-sectional study, 1536 serum proteins were assessed using the Olink Explore (Proximity Extension Assay) high-throughput panel in patients with moderate-to-severe HS (n = 11), patients with psoriasis (n = 10) and age- and body mass index-matched healthy controls (n = 10). Results HS displayed an overall greater dysregulation of circulating proteins, with 434 differentially expressed proteins (absolute fold change ≥ 1·2; P ≤ 0·05) in patients with HS vs. controls, 138 in patients with psoriasis vs. controls and 503 between patients with HS and patients with psoriasis. Interleukin (IL)-17A levels and T helper (Th)1/Th17 pathway enrichment were comparable between diseases, while HS presented greater tumour necrosis factor- and IL-1β-related signalling. The Th17-associated markers peptidase inhibitor 3 (PI3) and lipocalin 2 (LCN2) were able to differentiate psoriasis from HS accurately. Both diseases presented increases of atherosclerosis-related proteins. Robust correlations between clinical severity scores and immune and atherosclerosis-related proteins were observed across both diseases. Conclusions HS and psoriasis share significant Th1/Th17 enrichment and upregulation of atherosclerosis-related proteins. Despite the greater body surface area involved in psoriasis, HS presents a greater serum inflammatory burden.
Abstract 2595: Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature
Authors: Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman
Journal: Cancer Research (2021)

Abstract Background: Cancer patients experience cachexia which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. However, there are no approved treatments that can effectively counteract cancer cachexia. Prior research has focused on the changes within the muscle tissue but little is known about the role of the muscle vasculature in mediating cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply and preventing inappropriate transmigration of immune cells into the tissue. We therefore hypothesized that endothelial dysfunction in the skeletal muscle results in the development of cachexia in cancer. The transcriptional co-activator PGC1α (peroxisome proliferation activator receptor-γ coactivator1-α) regulates endothelial health. Methods and Results: To evaluate whether skeletal muscle EC-PGC1α is modulated in the setting of malignancy, we isolated muscle ECs from control and melanoma bearing mice at 1, 2, and 3 weeks after melanoma implantation. PGC1α expression was significantly decreased in mECs of melanoma bearing mice from early stage (1 week) compared with control mice. Thus, we generated an EC-specific inducible PGC1α deletion mouse model (ECΔPGC1α) to investigate the mechanistic role of EC-PGC1α in cancer cachexia in vivo. Interestingly, vascular density and muscle area were significantly decreased in the gastrocnemius (GC) of ECΔPGC1α mice compared with ECWT mice using an innovative tissue clearing and high-resolution 3D-tissue imaging system. Tumor bearing ECWT mice had decreased GC mass and weight compared with no tumor mice by enhancing cachexia marker genes, MuRF1 and Atrogin1. The tumor bearing ECΔPGC1α mice had further decreased muscle mass and weight, and grip strength than tumor bearing ECWT mice. We assessed the role of EC-PGC1α in the regulation of capillary function in vivo, and observed that ECΔPGC1α mice demonstrated significantly greater vascular leak than ECWT mice. Conclusion: These data suggest that the presence of melanoma suppresses PGC1α expression in the skeletal muscle endothelium. Endothelial PGC1α, in turn, is essential for maintaining the integrity of the skeletal muscle vascular barrier. Our study suggests that restoring muscle endothelial dysfunction could be a novel therapeutic approach to prevent or reverse cancer cachexia. Citation Format: Young-Mee Kim, Georgina Mancinelli, Paul Grippo, Jalees Rehman. Cancer cachexia is mediated by the suppression of PGC1-alpha expression in the skeletal muscle vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2595.
Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose–Response Evaluation
Authors: Erin E. Yost, Audrey Galizia, Dustin F. Kapraun, Amanda S. Persad, Suryanarayana V. Vulimiri, Michelle Angrish, Janice S. Lee, Ingrid L. Druwe
Journal: Environmental Health Perspectives (2021)

Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose-response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized.We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose-response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose-response analysis.Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381.
Abstract 3089: Study of HOX genes in the stem cell origin of CRC
Authors: Brian Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2021)

Abstract Our goal is to ascertain how HOX-regulatory mechanisms play a role in the SC origin of colorectal cancer (CRC). While HOX genes encode master regulatory transcription factors that regulate stem cells (SCs), their role in cancer etiology is under-studied. We and others find that HOX genes are aberrantly expressed in CRC. We previously reported that HOXA4 and HOXD10 along with aldehyde dehydrogenase (ALDH) and the other components of the retinoic acid (RA) signaling pathway are selectively expressed in human colon SCs. That RA signaling regulates HOX expression indicates that RA regulation of HOX gene expression mainly occurs through ALDH+ SCs in the colon. We hypothesize that specific HOX genes regulate growth and differentiation of SCs in human colon and HOX gene dysregulation leads to decreased differentiation and SC overpopulation. Indeed, our bioinformatics analysis shows that many HOX genes are overexpressed in CRCs, which parallels the overpopulation of ALDH+ SC that occurs during CRC tumorigenesis. We are using immunohistochemical mapping to measure proportions of SCs and HOX-positive cells in normal and malignant human colon tissues. We find that specific HOX proteins have increased expression levels in malignant colon tissues. In addition, immunofluorescence co-staining of human colon tissues is used to validate HOX gene expression in ALDH+ SCs. We are also evaluating the effects of all-trans-RA (ATRA) on HOX gene expression and on cellular proliferation and differentiation using CRC cell lines. Our results show that ATRA treatment of HT29 CRC cells leads to reduced proliferation and decreased expression of select HOX genes. These results indicate that HOX genes like HOXA4, HOXA9, and HOXD10, are expressed colonic SCs, and are regulated by RA signaling. Overall, the overexpression of HOX genes in cancer SCs appears to contribute to the SC origin of CRC. Citation Format: Brian Osmond, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Study of HOX genes in the stem cell origin of CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3089.
Abstract PL01-04: Epigenetic mechanisms of malignant clonal dominance and immune evasion
Authors: Mark A. Dawson
Journal: Cancer Research (2021)

Abstract All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary trajectories and clonal fitness imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. In this presentation I will discuss some of our recent work addressing the significance of transcriptional processes that facilitate malignant clonal dominance in isogenic cancer cells. I will also highlight emerging evidence showing the importance of manipulating transcriptional regulators to facilitate anti-cancer immune surveillance in a broad range of cancers. Citation Format: Mark A. Dawson. Epigenetic mechanisms of malignant clonal dominance and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL01-04.
Abstract 2293: Role of phosphatidylinositol 4-kinase IIIα in chemokine signaling
Authors: Barani Govindarajan, Sreenivasa Chinni, Diego Sbrissa
Journal: Cancer Research (2021)

Abstract The CXCR4-CXCL12 chemokine signaling axis plays a key role in migration and bone metastasis in prostate cancer (PC). Androgens regulate CXCR4 expression and its receptor activation in lipid-raft micro domains of PC cells, resulting in higher protease expression and invasion. In order to identify some novel CXCR4 co-regulators associated within the lipid-raft, a SILAC (Stable isotope labeling using amino acid in cell culture)-based proteomic analysis was performed with PC3 stable cell-lines over-expressing or knocking-down CXCR4. Phosphatidylinositol 4-kinase III alpha (PI4KIIIα or PI4KA) and SAC1 lipid phosphatase were identified as candidate proteins enriched in CXCR4 expressing cells. PI4KA is an evolutionarily conserved mammalian kinase that converts PI to PI4P; and SAC1 dephosphorylates PI4P to PI. PI4K is required for the maintenance and functioning of the plasma-membrane and vesicular trafficking in the Golgi apparatus. PI4KA is also needed to maintain a steady pool of PI(4,5)P2 in the plasma-membrane, to be utilized in various signaling pathways. We show that CXCR4 interacts with PI4KA through its adaptor proteins EFR3B and TTC7B, recruiting it to the plasma-membrane for PI4P generation. Similarly PI4KA was closely linked to CXCR4 induced PC cell invasion, and knockdown of PI4KA in CXCR4 over-expressing PC3 cell lines reduced cell invasion. Also localized productions of PI4P was evident in invasive projections of CXCR4 over-expressing cell lines through immunofluorescence microscopy. PC tumor microarray data show increased PI4K expression in metastatic PC tissue vs localized or normal adjacent tissue. These data suggest a novel interaction between PI4KA and CXCR4, promoting tumor cell invasion and metastasis. Pharmacological targeting of PI4KA, its adaptor proteins or its signaling-related proteins might prove therapeutically beneficial and enhance survival in PC patients. Citation Format: Barani Govindarajan, Sreenivasa Chinni, Diego Sbrissa. Role of phosphatidylinositol 4-kinase IIIα in chemokine signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2293.
Robot-assisted cystectomy and ileal conduit for neurogenic bladder: Comparison of extracorporeal vs intracorporeal urinary diversion
Authors: C. Mazouin, J. Hubert, T. Tricard, P. Lecoanet, C. Haudebert, I. Bentellis, P. Baron, J. Hascoet, C. Castes, B. Tibi, B. Pradere, F. Bruyere, G. Capon, A. Manunta, C. Saussine, B. Peyronnet
Journal: European Urology (2021)
The Effect of Epinephrine Dosing Intervals on Outcomes from Pediatric In-Hospital Cardiac Arrest
Authors: Martha F. Kienzle, Ryan W. Morgan, Jennifer A. Faerber, Kathryn Graham, Hannah Katcoff, William P. Landis, Alexis A. Topjian, Todd J. Kilbaugh, Vinay M. Nadkarni, Robert A. Berg, Robert M. Sutton
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Animal studies of cardiac arrest suggest that shorter epinephrine dosing intervals than currently recommended (every 3–5 min) may be beneficial in select circumstances. Objectives: To evaluate the association between epinephrine dosing intervals and pediatric cardiac arrest outcomes. Methods: Single-center retrospective cohort study of children (<18 years of age) who received ⩾1 minute of cardiopulmonary resuscitation and ⩾2 doses of epinephrine for an index in-hospital cardiac arrest. Exposure was epinephrine dosing interval ⩽2 minutes (frequent epinephrine) versus >2 minutes. The primary outcome was survival to hospital discharge with a favorable neurobehavioral outcome (Pediatric Cerebral Performance Category score 1–2 or unchanged). Logistic regression evaluated the association between dosing interval and outcomes; additional analyses explored duration of cardiopulmonary resuscitation (CPR) as a mediator. In a subgroup, the effect of dosing interval on diastolic blood pressure was investigated. Measurements and Main Results: Between January 2011 and December 2018, 125 patients met inclusion/exclusion criteria; 33 (26%) received frequent epinephrine. Frequent epinephrine was associated with increased odds of survival with favorable neurobehavioral outcome (adjusted odds ratio, 2.56; 95% confidence interval, 1.07–6.14; P = 0.036), with 66% of the association mediated by CPR duration. Delta diastolic blood pressure was greater after the second dose of epinephrine among patients who received frequent epinephrine (median [interquartile range], 6.3 [4.1 to 16.9] vs. 0.13 [−2.3 to 1.9] mm Hg; P = 0.034). Conclusions: In patients who received at least two doses of epinephrine, dosing intervals ⩽2 minutes were associated with improved neurobehavioral outcomes compared with dosing intervals >2 minutes. Mediation analysis suggests that improved outcomes are largely due to frequent epinephrine shortening duration of CPR.
Nocturnal polyuria is associated with worst functional outcomes after trans-urethral resection of prostate: A frequency volume chart study
Authors: C. De Nunzio, C. Polichetti, R. Lombardo, F. Cancrini, G. Tema, S. D’Annunzio, A. Nacchia, V. Baldassarri, B.C. Gentile, R. Giulianelli, A. Tubaro
Journal: European Urology (2021)
Foreword
Authors: J. Ingram
Journal: British Journal of Dermatology (2021)

This supplement contains abstracts of the papers and posters to be presented at the 101st Annual Meeting of the British Association of Dermatologists, to be held virtually, 6â€“8 July 2021. Also included are abstracts of the papers to be presented at the meetings of the following groups: British Society for Cutaneous Allergy, British Society for Dermatopathology, British Society for Dermatological Surgery, British Photodermatology Group, Historical Archive Collection, British Society for Skin Care in Immunosuppressed Individuals, Teledermatology and Digital Dermatology, British Cosmetic Dermatology Group, British Hair and Nail Society, Psychodermatolgy UK, British Society for Paediatric Dermatology, BADGEM and Dermatology Teachers sessions. In addition, abstracts of papers to be presented in the Health service delivery, management research and GIRFT symposium and Global Health Dermatology sessions are included.
Evaluation of the evolution of antibiotic prescription in the treatment of Healthcare-Associated Infections (HAIs) in a urology ward after implementing a treatment optimisation programme
Authors: J. Medina-Polo, P. Abad-López, A. González-Diaz, R. Santos-Pérez De La Blanca, M. Hernández-Arroyo, J. Teigell-Tobar, H. Peña-Vallejo, C. Calzas-Montalvo, M.P. Caro-González, N. Miranda-Uretra, J. Gil-Moradillo, Á. Tejido-Sánchez
Journal: European Urology (2021)
Determining a minimum set of variables for machine learning cardiovascular event prediction: results from REFINE SPECT registry
Authors: Richard Rios, Robert J H Miller, Lien Hsin Hu, Yuka Otaki, Ananya Singh, Marcio Diniz, Tali Sharir, Andrew J Einstein, Mathews B Fish, Terrence D Ruddy, Philipp A Kaufmann, Albert J Sinusas, Edward J Miller, Timothy M Bateman, Sharmila Dorbala, Marcelo DiCarli, Serge Van Kriekinge, Paul Kavanagh, Tejas Parekh, Joanna X Liang, Damini Dey, Daniel S Berman, Piotr Slomka
Journal: Cardiovascular Research (2021)

Optimal risk stratification with machine learning (ML) from myocardial perfusion imaging (MPI) includes both clinical and imaging data. While most imaging variables can be derived automatically, clinical variables require manual collection, which is time-consuming and prone to error. We determined the fewest manually input and imaging variables required to maintain the prognostic accuracy for major adverse cardiac events (MACE) in patients undergoing a single-photon emission computed tomography (SPECT) MPI.
The effectiveness of an electronic clinical-decision support tool embedded into the patient medical record at the point of care to guide Mohs surgery utilization: A cohort study
Authors: Sepideh Ashrafzadeh, Sameer Gupta, Anne-Maria Fiorino, Elizabeth T. Cafiero-Fonseca, Timothy G. Ferris, Maryam M. Asgari
Journal: Journal of the American Academy of Dermatology (2021)