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Article ; Online: In Search of Clinical Biomarkers of Response to Checkpoint Inhibitor Therapy in Renal Cell Carcinoma.

Fan, Alice C / Leppert, John T

JAMA network open

2021 Volume 4, Issue 1, Page(s) e2035120

MeSH term(s)	Apoptosis ; Biomarkers ; Carcinoma, Renal Cell/drug therapy ; Humans ; Kidney Neoplasms/drug therapy ; Ligands
Chemical Substances	Biomarkers ; Ligands
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2020.35120
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Article ; Online: Postmarketing Analysis of Sipuleucel-T-The Importance of Real-World Data.

Fan, Alice C / Leppert, John T

JAMA network open

2019 Volume 2, Issue 8, Page(s) e199233

MeSH term(s)	Humans ; Male ; Prostatic Neoplasms ; Tissue Extracts ; United States ; United States Food and Drug Administration
Chemical Substances	Tissue Extracts ; sipuleucel-T (8Q622VDR18)
Language	English
Publishing date	2019-08-02
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2019.9233
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Article ; Online: Targeting Metabolic Pathways in Kidney Cancer: Rationale and Therapeutic Opportunities.

Hoerner, Christian R / Miao, Susanna Y / Hsieh, James J / Fan, Alice C

Cancer journal (Sudbury, Mass.)

2021 Volume 26, Issue 5, Page(s) 407–418

Abstract: Alterations in cellular sugar, amino acid and nucleic acid, and lipid metabolism, as well as in mitochondrial function, are a hallmark of renal cell carcinoma (RCC). The activation of oncogenes such as hypoxia-inducible factor and loss of the von Hippel- ... ...

Abstract	Alterations in cellular sugar, amino acid and nucleic acid, and lipid metabolism, as well as in mitochondrial function, are a hallmark of renal cell carcinoma (RCC). The activation of oncogenes such as hypoxia-inducible factor and loss of the von Hippel-Lindau function and other tumor suppressors frequently occur early on during tumorigenesis and are the drivers for these changes, collectively known as "metabolic reprogramming," which promotes cellular growth, proliferation, and stress resilience. However, tumor cells can become addicted to reprogrammed metabolism. Here, we review the current knowledge of metabolic addictions in clear cell RCC, the most common form of RCC, and to what extent this has created therapeutic opportunities to interfere with such altered metabolic pathways to selectively target tumor cells. We highlight preclinical and emerging clinical data on novel therapeutics targeting metabolic traits in clear cell RCC to provide a comprehensive overview on current strategies to exploit metabolic reprogramming clinically.
MeSH term(s)	Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/metabolism ; Cell Proliferation ; Humans ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/metabolism ; Metabolic Networks and Pathways ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemical Substances	Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27)
Language	English
Publishing date	2021-02-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2018400-1
ISSN	1540-336X ; 1528-9117 ; 1081-4442
ISSN (online)	1540-336X
ISSN	1528-9117 ; 1081-4442
DOI	10.1097/PPO.0000000000000472
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Zs.A 4470: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 163: Show issues

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Article ; Online: Automated Image Analysis for Characterization of Circulating Tumor Cells and Clusters Sorted by Magnetic Levitation.

Ogut, Mehmet Giray / Ma, Peng / Gupta, Rakhi / Hoerner, Christian R / Fan, Alice C / El-Kaffas, Ahmed Nagy / Durmus, Naside Gozde

Advanced biology

2023 Volume 7, Issue 10, Page(s) e2300109

Abstract: Magnetic levitation-based sorting technologies have revolutionized the detection and isolation of rare cells, including circulating tumor cells (CTCs) and circulating tumor cell clusters (CTCCs). Manual counting and quantification of these cells are ... ...

Abstract	Magnetic levitation-based sorting technologies have revolutionized the detection and isolation of rare cells, including circulating tumor cells (CTCs) and circulating tumor cell clusters (CTCCs). Manual counting and quantification of these cells are prone to time-consuming processes, human error, and inter-observer variability, particularly challenging when heterogeneous cell types in 3D clusters are present. To overcome these challenges, we developed "Fastcount," an in-house MATLAB-based algorithm for precise, automated quantification and phenotypic characterization of CTCs and CTCCs, in both 2D and 3D. Fastcount is 120 times faster than manual counting and produces reliable results with a ±7.3% deviation compared to a trained laboratory technician. By analyzing 400 GB of fluorescence imaging data, we showed that Fastcount outperforms manual counting and commercial software when cells are aggregated in 3D or staining artifacts are present, delivering more accurate results. We further employed Fastcount for automated analysis of 3D image stacks obtained from CTCCs isolated from colorectal adenocarcinoma and renal cell carcinoma blood samples. Interestingly, we observed a highly heterogeneous spatial cellular composition within CTCCs, even among clusters from the same patient. Overall, Fastcount can be employed for various applications with lab-chip devices, such as CTC detection, CTCC analysis in 3D and cell detection in biosensors.
Language	English
Publishing date	2023-07-18
Publishing country	Germany
Document type	Journal Article
ISSN	2701-0198
ISSN (online)	2701-0198
DOI	10.1002/adbi.202300109
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Article: Proteomic Discovery of RNA-Protein Molecular Clamps Using a Thermal Shift Assay with ATP and RNA (TSAR).

Goldstein, Stanley I / Fan, Alice C / Wang, Zihao / Naineni, Sai K / Lengqvist, Johan / Chernobrovkin, Alexey / Garcia-Gutierrez, Steve B / Cencic, Regina / Patel, Kesha / Huang, Sidong / Brown, Lauren E / Emili, Andrew / Porco, John A

bioRxiv : the preprint server for biology

2024

Abstract: Uncompetitive inhibition is an effective strategy for suppressing dysregulated enzymes and their substrates, but discovery of suitable ligands depends on often-unavailable structural knowledge and serendipity. Hence, despite surging interest in mass ... ...

Abstract	Uncompetitive inhibition is an effective strategy for suppressing dysregulated enzymes and their substrates, but discovery of suitable ligands depends on often-unavailable structural knowledge and serendipity. Hence, despite surging interest in mass spectrometry-based target identification, proteomic studies of substrate-dependent target engagement remain sparse. Herein, we describe the Thermal Shift Assay with ATP and RNA (TSAR) as a template for proteome-wide discovery of substrate-dependent ligand binding. Using proteomic thermal shift assays, we show that simple biochemical additives can facilitate detection of target engagement in native cell lysates. We apply our approach to rocaglates, a family of molecules that specifically clamp RNA to eukaryotic translation initiation factor 4A (eIF4A), DEAD-box helicase 3X (DDX3X), and potentially other members of the DEAD-box (DDX) family of RNA helicases. To identify unexpected interactions, we optimized a target class-specific thermal denaturation window and evaluated ATP analog and RNA probe dependencies for key rocaglate-DDX interactions. We report novel DDX targets of the rocaglate clamping spectrum, confirm that DDX3X is a common target of several widely studied analogs, and provide structural insights into divergent DDX3X affinities between synthetic rocaglates. We independently validate novel targets of high-profile rocaglates, including the clinical candidate Zotatifin (
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.19.590252
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Article ; Online: Diverse and abundant phages exploit conjugative plasmids.

Quinones-Olvera, Natalia / Owen, Siân V / McCully, Lucy M / Marin, Maximillian G / Rand, Eleanor A / Fan, Alice C / Martins Dosumu, Oluremi J / Paul, Kay / Sanchez Castaño, Cleotilde E / Petherbridge, Rachel / Paull, Jillian S / Baym, Michael

Nature communications

2024 Volume 15, Issue 1, Page(s) 3197

Abstract: Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally encoded cell surface structures as receptors, plasmid-dependent phages exploit ...

Abstract	Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally encoded cell surface structures as receptors, plasmid-dependent phages exploit plasmid-encoded conjugation proteins, making their host range dependent on horizontal transfer of the plasmid. Despite their unique biology and biotechnological significance, only a small number of plasmid-dependent phages have been characterized. Here we systematically search for new plasmid-dependent phages targeting IncP and IncF plasmids using a targeted discovery platform, and find that they are common and abundant in wastewater, and largely unexplored in terms of their genetic diversity. Plasmid-dependent phages are enriched in non-canonical types of phages, and all but one of the 65 phages we isolated were non-tailed, and members of the lipid-containing tectiviruses, ssDNA filamentous phages or ssRNA phages. We show that plasmid-dependent tectiviruses exhibit profound differences in their host range which is associated with variation in the phage holin protein. Despite their relatively high abundance in wastewater, plasmid-dependent tectiviruses are missed by metaviromic analyses, underscoring the continued importance of culture-based phage discovery. Finally, we identify a tailed phage dependent on the IncF plasmid, and find related structural genes in phages that use the orthogonal type 4 pilus as a receptor, highlighting the evolutionarily promiscuous use of these distinct contractile structures by multiple groups of phages. Taken together, these results indicate plasmid-dependent phages play an under-appreciated evolutionary role in constraining horizontal gene transfer via conjugative plasmids.
MeSH term(s)	Bacteriophages/genetics ; Wastewater ; Biological Evolution ; Biotechnology ; Cell Membrane
Chemical Substances	Wastewater
Language	English
Publishing date	2024-04-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47416-z
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Article ; Online: The 'Achilles Heel' of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy.

Hoerner, Christian R / Chen, Viola J / Fan, Alice C

Kidney cancer (Clifton, Va.)

2019 Volume 3, Issue 1, Page(s) 15–29

Abstract: An important hallmark of cancer is 'metabolic reprogramming' or the rewiring of cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell ...

Abstract	An important hallmark of cancer is 'metabolic reprogramming' or the rewiring of cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.
Language	English
Publishing date	2019-02-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2961890-3
ISSN	2468-4570 ; 2468-4562
ISSN (online)	2468-4570
ISSN	2468-4562
DOI	10.3233/KCA-180043
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Article ; Online: Lay healthcare worker financial toxicity intervention: a pilot financial toxicity screening and referral program.

Parikh, Divya A / Rodriguez, Gladys M / Ragavan, Meera / Kerr, Elizabeth / Asuncion, Mary Khay / Hansen, Jennifer / Srinivas, Sandy / Fan, Alice C / Shah, Sumit / Patel, Manali I

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer

2024 Volume 32, Issue 3, Page(s) 161

Abstract: Purpose: Financial toxicity is a source of significant distress for patients with urologic cancers, yet few studies have addressed financial burden in this patient population.: Methods: We developed a financial toxicity screening program using a lay ... ...

Abstract	Purpose: Financial toxicity is a source of significant distress for patients with urologic cancers, yet few studies have addressed financial burden in this patient population. Methods: We developed a financial toxicity screening program using a lay health worker (LHW) and social worker (SW) to assess and mitigate financial toxicity in a single academic medical clinic. As part of a quality improvement project, the LHW screened all newly diagnosed patients with advanced stages of prostate, kidney, or urothelial cancer for financial burden using three COST tool questions and referred patients who had significant financial burden to an SW who provided personalized recommendations. The primary outcome was feasibility defined as 80% of patients with financial burden completing the SW consult. Secondary outcomes were patient satisfaction, change in COST Tool responses, and qualitative assessment of financial resources utilized. Results: The LHW screened a total of 185 patients for financial toxicity; 82% (n = 152) were male, 65% (n = 120) White, and 75% (n = 139) reported annual household income >$100,000 US Dollars; 60% (n = 114) had prostate cancer. A total of 18 (9.7%) participants screened positive for significant financial burden and were referred to the SW for consultation. All participants (100%) completed and reported satisfaction with the SW consultation and had 0.83 mean lower scores on the COST Tool post-intervention assessment compared to pre-intervention (95% confidence interval [0.26, 1.41]). Conclusion: This multidisciplinary financial toxicity intervention using an LHW and SW was feasible, acceptable, and associated with reduced financial burden among patients with advanced stages of urologic cancers. Future work should evaluate the effect of this intervention among cancer patients in diverse settings.
MeSH term(s)	Humans ; Male ; Financial Stress ; Health Personnel ; Referral and Consultation ; Urologic Neoplasms ; Prostatic Neoplasms
Language	English
Publishing date	2024-02-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1134446-5
ISSN	1433-7339 ; 0941-4355
ISSN (online)	1433-7339
ISSN	0941-4355
DOI	10.1007/s00520-024-08357-x
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Zs.A 3697: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Same-day post-therapy imaging with a new generation whole-body digital SPECT/CT in assessing treatment response to [

Song, Hong / Leonio, Maria Isabel / Ferri, Valentina / Duan, Heying / Aparici, Carina Mari / Davidzon, Guido / Franc, Benjamin L / Moradi, Farshad / Shah, Jagruti / Bergstrom, Colin P / Fan, Alice C / Shah, Sumit / Khaki, Ali Raza / Srinivas, Sandy / Iagaru, Andrei

European journal of nuclear medicine and molecular imaging

2024

Abstract: Purpose: Lutetium-177 [: Methods: In this retrospective study, 68 men with progressive mCRPC treated with [: Results: 56 patients (means age 76.2 ± 8.1 years, range: 60-93) who underwent at least 2 post-therapy SPECT/CT were included in the image ... ...

Abstract	Purpose: Lutetium-177 [ Methods: In this retrospective study, 68 men with progressive mCRPC treated with [ Results: 56 patients (means age 76.2 ± 8.1 years, range: 60-93) who underwent at least 2 post-therapy SPECT/CT were included in the image analysis. The whole-body SPECT/CT scans (~ 12 min per scan) were well tolerated, with 221 same-day scans performed (89%). At a median of 10-months follow-up, 33 (58.9%) patients achieved PSA50 after [ Conclusion: We successfully implemented same-day post-therapy SPECT/CT after [
Language	English
Publishing date	2024-04-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	8236-3
ISSN	1619-7089 ; 0340-6997 ; 1619-7070
ISSN (online)	1619-7089
ISSN	0340-6997 ; 1619-7070
DOI	10.1007/s00259-024-06718-6
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Zs.A 1227: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article: Diverse and abundant phages exploit conjugative plasmids.

bioRxiv : the preprint server for biology

2023

Abstract: Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally-encoded cell surface structures as receptors, plasmid-dependent phages exploit ...

Abstract	Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally-encoded cell surface structures as receptors, plasmid-dependent phages exploit plasmid-encoded conjugation proteins, making their host range dependent on horizontal transfer of the plasmid. Despite their unique biology and biotechnological significance, only a small number of plasmid-dependent phages have been characterized. Here we systematically search for new plasmid-dependent phages targeting IncP and IncF plasmids using a targeted discovery platform, and find that they are common and abundant in wastewater, and largely unexplored in terms of their genetic diversity. Plasmid-dependent phages are enriched in non-canonical types of phages, and all but one of the 64 phages we isolated were non-tailed, and members of the lipid-containing tectiviruses, ssDNA filamentous phages or ssRNA phages. We show that plasmid-dependent tectiviruses exhibit profound differences in their host range which is associated with variation in the phage holin protein. Despite their relatively high abundance in wastewater, plasmid-dependent tectiviruses are missed by metaviromic analyses, underscoring the continued importance of culture-based phage discovery. Finally, we identify a tailed phage dependent on the IncF plasmid, and find related structural genes in phages that use the orthogonal type 4 pilus as a receptor, highlighting the promiscuous use of these distinct contractile structures by multiple groups of phages. Taken together, these results indicate plasmid-dependent phages play an under-appreciated evolutionary role in constraining horizontal gene transfer via conjugative plasmids.
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.19.532758
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