tbuckley/cabot-search huggingface dataset:
The efficacy of bevacizumab plus erlotinib (B+E) in patients (pts) with renal medullary carcinoma (RMC).
Authors: Andrew James Wiele, Devaki Shilpa Surasi, Priya Rao, Kanishka Sircar, Tharakeswara Bathala, Amishi Yogesh Shah, Eric Jonasch, Vince David Cataldo, Giannicola Genovese, Jose A. Karam, Christopher G. Wood, Nizar M. Tannir, Pavlos Msaouel
Journal: Journal of Clinical Oncology (2021)

303 Background: RMC is a rare and highly aggressive malignancy with a median overall survival (OS) of only 13 months from diagnosis. RMC is thought to be completely refractory to the targeted therapies used against clear cell renal cell carcinoma and the recommended standard of care therapy is platinum-based cytotoxic chemotherapy, which only produces a best response rate of 29% in the first line setting (Shah et al. BJU Int., 2017). Comprehensive molecular profiling of RMC tissues revealed a decrease in genes related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and an increase in genes involved in fatty acid synthesis, demonstrating a reliance on aerobic glycolysis to meet cellular bioenergetics needs (Msaouel et al. Cancer Cell, 2020). The combination of B+E is particularly effective in tumors such as fumarate hydratate – deficient renal cell carcinomas, which also rely on aerobic glycolysis. We therefore hypothesized that B+E would show clinical efficacy against RMC. Methods: We analyzed 10 pts with RMC treated with B+E at our institution. A blinded board-certified radiologist reviewed all restaging images to assess best radiographic response as defined by RECIST v1.1 and, when applicable, date of progression. Adverse events (AEs) were evaluated using the CTCAE version 5.0 grading estimated from chart documentation. Clinical-grade next generation genome sequencing for gene mutations, copy number alterations and fusions was performed in 6/10 pts using the Oncomine platform. Results: Between 05/2005 and 09/2020, we identified 10 pts with RMC that were treated with B+E (Table). B+E produced a partial response in 2/10 pts (20%) and stable disease as best response in 6/10 pts (60%), resulting in a median progression-free survival of 3.5 months (mo) with 95% CI 1.8 – 5.2 mo. Decrease in tumor burden was noted even in patients that had received 3+ prior therapies and irrespective of genomic alterations. The median overall survival (OS) from B+E initiation was 7.3 mo (95% CI 5.4 – 9.1) and the median OS from diagnosis was 20.8 mo (95% CI 15.4 – 26.1). B+E was well tolerated with no grade ≥ 4 AEs and only one grade 3 AE (skin rash). Dose reduction was only needed in 1/10 pts. Conclusions: B+E is clinically active and well tolerated in heavily pre-treated pts with RMC and is therefore a viable therapeutic option for this lethal disease. However, pts ultimately relapse and further investigation is needed to elucidate mechanisms of resistance and determine how to optimally target metabolic vulnerabilities in RMC. [Table: see text]
Patient-Derived Organoids for Precision Cancer Immunotherapy
Authors: Mikaela Grönholm, Michaela Feodoroff, Gabriella Antignani, Beatriz Martins, Firas Hamdan, Vincenzo Cerullo
Journal: Cancer Research (2021)

Abstract Cancer immunotherapy has revolutionized the way tumors are treated. Nevertheless, efficient and robust testing platforms are still missing, including clinically relevant human ex vivo tumor assays that allow pretreatment testing of cancer therapies and selection of the most efficient and safe therapy for a specific patient. In the case of immunotherapy, this testing platform would require not only cancer cells, but also the tumor microenvironment, including immune cells. Here, we discuss the applications of patient-derived tumor organoid cultures and the possibilities in using complex immune–organoid cultures to provide preclinical testing platforms for precision cancer immunotherapy.
A Comprehensive Map of mRNAs and Their Isoforms across All 14 Renal Tubule Segments of Mouse
Authors: Lihe Chen, Chun-Lin Chou, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2021)

The repertoire of protein expression along the renal tubule depends both on regulation of transcription and regulation of alternative splicing that can generate multiple proteins from a single gene.A full-length, small-sample RNA-seq protocol profiled transcriptomes for all 14 renal tubule segments microdissected from mouse kidneys.This study identified >34,000 transcripts, including 3709 that were expressed in a segment-specific manner. All data are provided as an online resource (https://esbl.nhlbi.nih.gov/MRECA/Nephron/). Many of the genes expressed in unique patterns along the renal tubule were solute carriers, transcription factors, or G protein-coupled receptors that account for segment-specific function. Mapping the distribution of transcripts associated with Wnk-SPAK-PKA signaling, renin-angiotensin-aldosterone signaling, and cystic diseases of the kidney illustrated the applications of the online resource. The method allowed full-length mapping of RNA-seq reads, which facilitated comprehensive, unbiased characterization of alternative exon usage along the renal tubule, including known isoforms of Cldn10, Kcnj1 (ROMK), Slc12a1 (NKCC2), Wnk1, Stk39 (SPAK), and Slc14a2 (UT-A urea transporter). It also identified many novel isoforms with segment-specific distribution. These included variants associated with altered protein structure (Slc9a8, Khk, Tsc22d1, and Scoc), and variants that may affect untranslated, regulatory regions of transcripts (Pth1r, Pkar1a, and Dab2).Full-length, unbiased sequencing of transcripts identified gene-expression patterns along the mouse renal tubule. The data, provided as an online resource, include both quantitative and qualitative differences in transcripts. Identification of alternative splicing along the renal tubule may prove critical to understanding renal physiology and pathophysiology.
Abstract PR-11: Developing an agnostic risk prediction model for acute kidney injury in cancer patients using a machine learning algorithm from blood results data
Authors: Lauren A. Scanlon, Jorge Barrusio, Alexander Garbett
Journal: Clinical Cancer Research (2021)

Abstract Acute Kidney Injury (AKI) is a common complication in hospital inpatients with the annual number of excess inpatient deaths associated with AKI in England estimated to be above 40,000 and the annual cost of AKI-related inpatient care around £1.02 billion. Oncology patients are a known high risk population for developing AKI. The prevalence of AKI in oncology populations is 7.5 to 9.5%, with AKI incidence associated with lower remission rates and higher mortality. To reduce the impact of this condition in cancer patients we aimed to create a model to predict AKI events before occurrence allowing intervention and prevention strategies to be put in place. We trained a Random Forest Model on 597,403 blood test results from 48,865 patients undergoing cancer treatment at The Christie NHS Foundation Trust, Manchester, UK between January 2017 and 3rd May 2020, to identify AKI events upcoming in the next 30 days. From this model, risk levels of very low, low, medium, high and very high were assigned to the risk of an upcoming AKI event. We tested the model and risk assessment through a prospective analysis on patients’ blood tests results collected between 1st June 2020 to 31st August 2020. The trained model gave an area under the receiver operating characteristic curve (ROC AUC) of 88.1% (95% confidence interval 87.8% - 88.3%) when assessing predictions per blood test for AKI occurrences within 30 days. Assigning risk levels and testing the model through prospective validation across the period 1st June to the 31st August identified 61.2% of AKI occurrences with a risk alert of `Medium' or higher, identifying 73.8% of patients with AKI event before at least one AKI occurrence. Our results demonstrate the exciting potential for using routinely collected blood test data to assign AKI risk levels allowing early intervention and preventative strategies to be put in place. Citation Format: Lauren A. Scanlon, Jorge Barrusio, Alexander Garbett. Developing an agnostic risk prediction model for acute kidney injury in cancer patients using a machine learning algorithm from blood results data [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-11.
Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice
Authors: Michaela A.A. Fuchs, Katharina A.E. Broeker, Julia Schrankl, Nicolai Burzlaff, Carsten Willam, Charlotte Wagner, Armin Kurtz
Journal: Kidney International (2021)

Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor β1 (TGFβ1) is considered a central trigger for kidney fibrosis. We found a highly upregulated expression of TGFβ1 and TGFβ receptor 2 (TGFβ-R2) mRNAs in kidney interstitial cells in experimental fibrosis. Here, we investigated the contribution of TGFβ1 signaling in resident kidney interstitial cells to organ fibrosis using the models of adenine induced nephropathy and unilateral ureteral occlusion in mice. For this purpose TGFβ1 signaling was interrupted by inducible deletion of the TGFβ-R2 gene in interstitial cells expressing the fibroblast marker platelet derived growth factor receptor-β. Expression of profibrotic genes was attenuated up to 50% in kidneys lacking TGFβ-R2 in cells positive for platelet derived growth factor receptor-β. Additionally, deletion of TGFβ-R2 prevented the decline of erythropoietin production in ureter ligated kidneys. Notably, fibrosis associated expression of α-smooth muscle actin as a myofibroblast marker and deposits of extracellular collagens were not altered in mice with targeted deletion of TGFβ-R2. Thus, our findings suggest an enhancing effect of TGFβ1 signaling in resident interstitial cells that contributes to profibrotic gene expression and the downregulation of erythropoietin production, but not to the development of myofibroblasts during kidney fibrosis.
Shaken baby syndrome * Authors' reply
Authors: J. B P Stephenson, M. Sandberg, R. Minns, R. G Barr
Journal: Journal of the Royal Society of Medicine (2003)

Dr Jackson and Dr Warner highlight worrying deficiencies in clinicians' judgments on capacity and consent to treatment (December 2002 JRSM 1 ).Unfortunately, their summary may further confuse matters by stating that, '15% of all respondents wrongly believed that a competent adult could lawfully be treated against his or her will'.In fact, competent adults can be lawfully treated against their will, in certain clearly defined circumstances.The key omission here is the phrase, 'under common law' (which was included in the question posed to doctors).This was no doubt an oversight, but it draws attention to a related concernnamely, that doctors (and medical students) often seem to conflate judgments about capacity and the common law with judgments about mental disorder and the Mental Health Act, when discussing whether patients can be treated without their consent.In fact such judgments should be clearly distinct.Someone with a mental disorder who is detained under the Act may still meet the capacity criteria (and thereby be judged competent) to consent to, or refuse, certain medical treatments 2 .Contrariwise, an individual without a mental disorder may fail to meet the capacity threshold, and be deemed incompetent.Jackson and Warner also found that medical students were very poor at identifying the criteria for capacity, with only 15% doing so correctly.That students are misinformed about issues of medical ethics and law is not surprising.In a recent teaching session, a senior doctor insisted to our group that in England an adult (such as a spouse) could consent to medical treatment on behalf of another adult.Until the teachers are correctly informed about these important issues, what hope for their students?
39P Effect of dose level of the selective FGFR2 inhibitor alofanib on toxicity, pharmacokinetics and preliminary efficacy: A phase Ib study in patients with advanced gastric cancer (RPT835GC1B)
Authors: I. Tsimafeyeu, V. Kazey, N. Dragun, D. Reznikov, E. Gavrilova, S. Gorbacheva, A. Nikiforova, M. Byakhov, S. Tjulandin
Journal: Annals of Oncology (2021)
Stress‐Responsive Gene FK506‐Binding Protein 51 Mediates Alcohol‐Induced Liver Injury Through the Hippo Pathway and Chemokine (C‐X‐C Motif) Ligand 1 Signaling
Authors: Praveen Kusumanchi, Tiebing Liang, Ting Zhang, Ruth Ann Ross, Sen Han, Kristina Chandler, Adepeju Oshodi, Yanchao Jiang, Alexander L. Dent, Nicholas J. Skill, Nazmul Huda, Jing Ma, Zhihong Yang, Suthat Liangpunsakul
Journal: Hepatology (2021)

Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD.We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model.We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.
Abstract PO-068: Developing ovarian cancer sensors using molecular perceptron
Authors: Zvi Yaari, Yoona Yang, Anand Jagota, Ming Zheng, Daniel A. Heller
Journal: Clinical Cancer Research (2021)

Abstract Ovarian cancer patient prognosis and quality of life are significantly affected by the failure to accurately diagnose disease at early stage. Currently, less than 15% of ovarian cancer patients are diagnosed at stage 1, when 5-year survival rates are near 93%. Early detection may save more than 80% of women diagnosed with ovarian cancer. Our goal is to develop clinical long-term implantable carbon nanotube-based sensors for ovarian cancer biomarkers to transiently detect and monitor their levels in patients. The proposed sensors will harness the unique optical properties and sensitivity of single-walled carbon nanotubes. To improve sensitivity and specificity of such sensors, previously developed to detect ovarian cancer biomarkers in vivo, we used molecular perceptron—data analytics-based methods to detect specific spectroscopic fingerprints from the binding of protein biomarkers to the nanotube surface. Citation Format: Zvi Yaari, Yoona Yang, Anand Jagota, Ming Zheng, Daniel A. Heller. Developing ovarian cancer sensors using molecular perceptron [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-068.
Economic evaluation of whole genome sequencing for pathogen identification and surveillance – results of case studies in Europe and the Americas 2016 to 2019
Authors: Frank Alleweldt, Şenda Kara, Kris Best, Frank M Aarestrup, Martin Beer, Theo M Bestebroer, Josefina Campos, Gabriele Casadei, Isabel Chinen, Gary Van Domselaar, Catherine Dominguez, Helen E Everett, Ron AM Fouchier, Kathie Grant, Jonathan Green, Dirk Höper, Jonathan Johnston, Marion PG Koopmans, Bas B Oude Munnink, Robert Myers, Celine Nadon, Ami Patel, Anne Pohlmann, Stefano Pongolini, Aleisha Reimer, Shane Thiessen, Claudia Wylezich
Journal: Eurosurveillance (2021)

BackgroundWhole genome sequencing (WGS) is increasingly used for pathogen identification and surveillance.AimWe evaluated costs and benefits of routine WGS through case studies at eight reference laboratories in Europe and the Americas which conduct pathogen surveillance for avian influenza (two laboratories), human influenza (one laboratory) and food-borne pathogens (five laboratories).MethodsThe evaluation focused on the institutional perspective, i.e. the 'investment case' for implementing WGS compared with conventional methods, based on costs and benefits during a defined reference period, mostly covering at least part of 2017. A break-even analysis estimated the number of cases of illness (for the example of Salmonella surveillance) that would need to be avoided through WGS in order to 'break even' on costs.ResultsOn a per-sample basis, WGS was between 1.2 and 4.3 times more expensive than routine conventional methods. However, WGS brought major benefits for pathogen identification and surveillance, substantially changing laboratory workflows, analytical processes and outbreaks detection and control. Between 0.2% and 1.1% (on average 0.7%) of reported salmonellosis cases would need to be prevented to break even with respect to the additional costs of WGS.ConclusionsEven at cost levels documented here, WGS provides a level of additional information that more than balances the additional costs if used effectively. The substantial cost differences for WGS between reference laboratories were due to economies of scale, degree of automation, sequencing technology used and institutional discounts for equipment and consumables, as well as the extent to which sequencers are used at full capacity.
Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment
Authors: Kristen E. Pauken, Osmaan Shahid, Kaitlyn A. Lagattuta, Kelly M. Mahuron, Jacob M. Luber, Margaret M. Lowe, Linglin Huang, Conor Delaney, Jaclyn M. Long, Megan E. Fung, Kathleen Newcomer, Katy K. Tsai, Melissa Chow, Samantha Guinn, Juhi R. Kuchroo, Kelly P. Burke, Jason M. Schenkel, Michael D. Rosenblum, Adil I. Daud, Arlene H. Sharpe, Meromit Singer
Journal: The Journal of Experimental Medicine (2021)

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.
Characterization of initial key steps of IL-17 receptor B oncogenic signaling for targeted therapy of pancreatic cancer
Authors: Heng-Hsiung Wu, Lung-Hung Tsai, Chun-Kai Huang, Pang-Hung Hsu, Mei-Yu Chen, Yi-Ing Chen, Chun-Mei Hu, Chia-Ning Shen, Chen-Chen Lee, Ming-Chu Chang, Yu-Ting Chang, Yu-Wen Tien, Yung-Ming Jeng, Eva Y.-H.P. Lee, Wen-Hwa Lee
Journal: Science Translational Medicine (2021)

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.
Incidental 18F-Florapronol Uptake in Meningioma
Authors: Inki Lee, Joon Seog Kong, Sang Min Youn, Ilhan Lim, Jeong Ho Ha
Journal: Clinical Nuclear Medicine (2021)

Abstract A 76-year-old woman underwent 18 F-florapronol ( 18 F-FC119S, an amyloid β imaging PET agent) PET, owing to cognitive impairment. 18 F-florapronol PET images revealed an incidental 18 F-florapronol uptake in the right frontal lobe. A well-enhancing extra-axial mass in the right frontal lobe was observed on MRI scans, suggesting a meningioma. After excision of the tumor, the biopsy results confirmed it as a meningothelial meningioma.
Minimalist Tissue Engineering Approaches Using Low Material‐Based Bioengineered Systems
Authors: Clara R. Correia, Isabel M. Bjørge, Sara Nadine, João F. Mano
Journal: Advanced Healthcare Materials (2021)

Abstract From an “over‐engineering” era in which biomaterials played a central role, now it is observed to the emergence of “developmental” tissue engineering (TE) strategies which rely on an integrative cell‐material perspective that paves the way for cell self‐organization. The current challenge is to engineer the microenvironment without hampering the spontaneous collective arrangement ability of cells, while simultaneously providing biochemical, geometrical, and biophysical cues that positively influence tissue healing. These efforts have resulted in the development of low‐material based TE strategies focused on minimizing the amount of biomaterial provided to the living key players of the regenerative process. Through a “minimalist‐engineering” approach, the main idea is to fine‐tune the spatial balance occupied by the inanimate region of the regenerative niche toward maximum actuation of the key living components during the healing process.