tbuckley/cabot-search huggingface dataset:
Successful Introduction of Human Renovascular Units into the Mammalian Kidney
Authors: Oren Pleniceanu, Orit Harari-Steinberg, Dorit Omer, Yehudit Gnatek, Bat-El Lachmi, Osnat Cohen-Zontag, Eugenia Manevitz-Mendelson, Aviv Barzilai, Matan Yampolsky, Yaron Fuchs, Barak Rosenzweig, Alon Eisner, Zohar Dotan, Leon G. Fine, Benjamin Dekel, Shoshana Greenberger
Journal: Journal of the American Society of Nephrology (2020)

Cell-based therapies aimed at replenishing renal parenchyma have been proposed as an approach for treating CKD. However, pathogenic mechanisms involved in CKD such as renal hypoxia result in loss of kidney function and limit engraftment and therapeutic effects of renal epithelial progenitors. Jointly administering vessel-forming cells (human mesenchymal stromal cells [MSCs] and endothelial colony-forming cells [ECFCs]) may potentially result in in vivo formation of vascular networks.We administered renal tubule-forming cells derived from human adult and fetal kidneys (previously shown to exert a functional effect in CKD mice) into mice, alongside MSCs and ECFCs. We then assessed whether this would result in generation of "renovascular units" comprising both vessels and tubules with potential interaction.Directly injecting vessel-forming cells and renal tubule-forming cells into the subcutaneous and subrenal capsular space resulted in self-organization of donor-derived vascular networks that connected to host vasculature, alongside renal tubules comprising tubular epithelia of different nephron segments. Vessels derived from MSCs and ECFCs augmented in vivo tubulogenesis by the renal tubule-forming cells. In vitro coculture experiments showed that MSCs and ECFCs induced self-renewal and genes associated with mesenchymal-epithelial transition in renal tubule-forming cells, indicating paracrine effects. Notably, after renal injury, renal tubule-forming cells and vessel-forming cells infused into the renal artery did not penetrate the renal vascular network to generate vessels; only administering them into the kidney parenchyma resulted in similar generation of human renovascular units in vivo.Combined cell therapy of vessel-forming cells and renal tubule-forming cells aimed at alleviating renal hypoxia and enhancing tubulogenesis holds promise as the basis for new renal regenerative therapies.
Abstract B23: EWS-FLI1 partners with EWSR1 to regulate transcription in Ewing sarcoma
Authors: Nasiha Ahmed, Jacob Schwartz
Journal: Cancer Research (2020)

Abstract Transcription factors are important regulators in normal cell proliferation and cancer. Ewing sarcoma is a pediatric bone cancer driven by a translocation between two transcription factor genes, EWSR1 and FLI1, leading to the expression of an aberrant transcription factor, EWS-FLI1. While FLI1 is not expressed, constitutive expression of EWSR1 is retained in Ewing sarcoma cells. However, very little is known about the effect of wild-type EWSR1 on EWS-FLI1 transcriptional activity. EWSR1 and EWS-FLI1 coimmunoprecipitate in a complex together in Ewing sarcoma cells and HEK293T cells. RNA-sequencing in Ewing sarcoma cells revealed a pool of genes coregulated by EWS-FLI1 and EWSR1. Furthermore, loss of EWSR1 in Ewing sarcoma cells inhibits anchorage-independent growth. Taken together, this suggests EWSR1 may play a key role in the transcriptional activity of EWS-FLI1 in Ewing sarcoma biology. Citation Format: Nasiha Ahmed, Jacob Schwartz. EWS-FLI1 partners with EWSR1 to regulate transcription in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B23.
Effective notification systems should be streamlined for the pandemic, not discarded
Authors: John Ashcroft
Journal: BMJ (2020)

In theory, the UK has a comprehensive notification system, set in statute, whereby all clinically suspected cases of covid-19, as well as laboratory diagnosed cases, should be notified to local public health services. Roderick and colleagues document that this is failing in practice.1

This failure is no more apparent than in the recent events in Leicester. Matt Hancock, secretary …
Resonant images from the United States
Authors: G. C S Smith
Journal: BMJ (1997)

The path to America is well trodden by middle grade medical staff from Britain. They return with fishermen's tales of the fabled inefficient, overinvestigating American healthcare system—“and they ordered whole body magnetic resonance imaging for an ingrowing toenail.” Such tales of the disaffected can get their authors in trouble, like the recent rebuke in the BMJ from the president of the American Society of Anesthesiologists over accusations from a visiting British registrar that American anaesthetists were dictated to by surgeons—perhaps the president of the American College of Surgeons told him to write the letter.

Coming to Cornell University in Ithaca, New York, for three years of basic science research, I was quietly smug that such tedious anecdotes would not issue from me. And then my 5 year old daughter developed a fever of 100°F and the inability to bear weight on her right leg.

Our first port of call was the local casualty department. No history or signs of trauma, both ankle joints clinically normal, tender over the distal tibia on …
What are the best endpoints for Eczema Area and Severity Index and Scoring Atopic Dermatitis in clinical practice? A prospective observational study*
Authors: J.I. Silverberg, D. Lei, M. Yousaf, S.R. Janmohamed, P.P. Vakharia, R. Chopra, R. Chavda, S. Gabriel, K.R. Patel, V. Singam, R. Kantor, D.Y. Hsu
Journal: British Journal of Dermatology (2020)

Multiple strategies have been used to evaluate the minimal important change (MIC) of the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD). The meaningfulness of these MICs is not well established across all severities of atopic dermatitis (AD). To determine the MIC of percentage and absolute improvement of EASI and SCORAD scores in adults and children with AD. We performed a prospective dermatology practice‐based study using questionnaires and evaluation by a dermatologist (n = 826). An anchor‐based approach was used to determine thresholds for the percentage and absolute MICs of EASI, SCORAD and objective SCORAD (O‐SCORAD) at follow‐up from baseline. One‐grade improvements of Physician's Global Assessment (PGA) and validated Investigator Global Assessment scale for AD (vIGA‐AD) were associated with 50%, 35% and 35% decreases of EASI, SCORAD and O‐SCORAD, respectively. The thresholds for percentage MIC of EASI (Kruskal–Wallis test, P = 0·61), SCORAD (P = 0·07) and O‐SCORAD (P = 0·09) were similar across baseline AD severities. One‐grade improvements of PGA and vIGA‐AD were associated with 14·0‐ and 14·9‐point decreases of EASI, 19·9‐ and 14·9‐point decreases of SCORAD, and 15·5‐ and 17·4‐point decreases of O‐SCORAD. The thresholds for the absolute MIC of EASI (P < 0·001), SCORAD (P < 0·001) and O‐SCORAD (P < 0·001) significantly differed by baseline AD severity. Percentage and absolute MICs for EASI and SCORAD were associated with improvements of AD symptoms and quality of life. EASI 50, SCORAD 35 and O‐SCORAD 35 were meaningful percentage MICs regardless of baseline AD severity. The absolute MICs for EASI, SCORAD and O‐SCORAD varied by baseline AD severity.
THU0253 Synoviocyte Apoptosis May Differentiate Responder and Non-Responder Patients to Methotrexate Treatment in Rheumatoid Arthritis
Authors: S. Y. Lee, J. H. Bae, S. W. Lee, W. T. Chung
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> there is no study reporting whether MTX inhibits rheumatoid synovitis by inducing apoptosis of synoviocytes, depending on the clinical sensitivity of MTX. <h3>Objectives</h3> We aimed to evaluate whether MTX <i>in vitro</i> induces apoptosis in synoviocytes obtained from rheumatoid arthritis patients and whether the apoptosis inducing effect of MTX to synoviocytes is correlated with the clinical responsiveness to MTX in patients with RA. <h3>Methods</h3> We evaluated 10 patients with RA taking MTX 15-20 mg/week as the subject group (5 responders and 5 non-responders) and 5 patients with osteoarthritis (OA) and 3 patients with ankylosing spondylitis (AS) as the control group. Synoviocytes, cultured from the synovial fluid of the knee joint of each subject, were used for experiments between passages 4 and 6, and were treated with MTX. The induction of apoptosis was determined by the quantification of DNA hypoploidy by flow cytometry, nuclear morphology, caspases activation, DNA electrophoresis, and mitochondrial membrane potential measurements. <h3>Results</h3> The viability of synoviocytes treated with MTX was different between the MTX responders and nonresponders. MTX induced apoptosis in cultured synoviocytes by mitochondria- and caspase-dependent manners in the MTX responders but did not in the MTX non-responder, OA, and AS patients. <h3>Image/graph</h3> <h3>Conclusions</h3> The apoptotic responsiveness of the synoviocytes to MTX predicts the sensitivity to MTX treatment and provides a method determine the early application of TNF-α agent in RA treatment. <h3>References</h3> Wessels JA, et al(2008) Rheumatology 47, 249-55 <h3>Disclosure of Interest</h3> None Declared
Phenoxodiol phase Ib/II study in patients with recurrent ovarian cancer that are resistant to ≥ second line chemotherapy
Authors: Thomas Rutherford, David O’malley, Anita Makkenchery, Lisa Baker, Masoud Azodi, Peter Schwartz, Gil Mor
Journal: Cancer Research (2004)

4457  Introduction: Resistance to apoptosis is a critical step in cancer development and chemoresistance. Apoptosis-based tumor therapy represents a new and promising approach for the treatment of cancer. Recently we have shown that Phenoxodiol (Ph) selectively removes blockers of apoptosis in chemo resistant ovarian cancer cells and inhibits tumor growth in vivo. Phase I studies with Ph have shown no-toxicity in patients with solid tumors. The objective of this study was to evaluate the toxicity and preliminary efficacy of Ph in recurrent ovarian cancer. Methods: Forty patients with documented recurrence after second line chemotherapy and histologically confirmed epithelial ovarian, fallopian or primary peritoneal cancer were eligible for this study. Patients were randomized at four dose levels (1, 3, 10, 20 mg/kg), ten patients per dose, and received treatment consisting of bolus Ph weekly on 2 consecutive days. Toxicity was scored according to NCI criteria. Response was defined according to Recist criteria in patients with measurable disease or Rustin criteria in evaluable patients with CA125 criteria. Results: To date, we have completed enrollment of this trial and data is currently available for the twenty patients in the first two dose levels (1and 3 mg/kg). The median number of prior chemotherapy regiments was 5 (range: 2 –10). 18 patients were platinum refractory or resistant and 2 patients could not be assessed. 18/20 patients had measurable disease. There were no toxicities related to Ph therapy. In the first dose strata (1 mg/kg), 7/10 patients completed 12 weeks of treatment and 2 patients had stable disease at 12 weeks. 6/7 patients are alive (303 ± 15 days) and under different treatment. In the second dose strata (3 mg/kg), 6/10 patients completed 12 weeks of treatment and 3 patients had stable disease at 12 weeks. 5/6 patients are alive (268± 20 days) and under different treatment. Conclusion: Phenoxodiol was found to be very well tolerated at the dose levels reported here in, with no documented toxicities. In these heavily pre-treated patients, stable disease was documented in 25% of patients. No objective responses were observed. We expect the data on the third and fourth dose levels to be available shortly. A clinical protocol is currently being designed to combine Phenoxodiol with standard chemotherapies.
Epidemiologic and microbiologic correlates of Chlamydia trachomatis infection in sexual partnerships
Authors: T. C. Quinn
Journal: JAMA (1996)

Objective.  —To determine the frequency of Chlamydia trachomatis genital infection within sexual partnerships using highly sensitive polymerase chain reaction (PCR) amplification and to identify the variables that might modify transmission.  Design.  —Cross-sectional study of sexual partnerships comparing in vitro culture and PCR amplification for C trachomatis .  Setting.  —Two outpatient sexually transmitted disease clinics.  Participants.  —Four hundred ninety-four people in sexual partnerships attending sexually transmitted disease clinics.  Main Outcome Measure.  —Genital infection with C trachomatis.  Methods.  —DNA sequencing was performed to examine specific genotypes within and between partnerships. Cross-sectional analysis was performed to determine characteristics associated with concordance or discordance of infection with partnerships.  Results.  —Cultures were positive for C trachomatis in 8.5% of males and 12.9% of females ( P =.03). Using PCR, more infections were identified both in males (14.2%) and in females (15.8%), and the difference in infection rates analyzed by sex was no longer significant. In 20.4% of 494 couples, at least 1 partner had PCR results positive for C trachomatis , with a concordant infection rate of 10.7%, significantly higher than the 5.5% concordant infection rate demonstrable by culture ( P   Conclusions.  —Using PCR, the frequency of chlamydia transmission by infected males and females was nearly identical. The high rate of concordant infection, high frequency of infection among asymptomatic individuals, and high frequency of transmission regardless of sex underscore the importance of routine screening for chlamydia in both males and females, along with provision of treatment to all sexual partners of chlamydia-infected individuals.
Abstract B21: Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment response
Authors: Huwate Yeerna, Benjamin Briggs, Jessica Rusert, Lukas Chavez, Jill Mesirov, Robert Wechsler-Reya, Pablo Tamayo
Journal: Cancer Research (2020)

Abstract Background: Medulloblastoma is a heterogenous group of tumors that collectively are the most common malignant brain tumor of childhood. Advances in treatment are required as one third of patients die from the disease, and those who survive suffer severe long-term side effects from therapy. The ability to sequence entire genome, methylome, and transcriptome of tumors provides the opportunity to identify underlying drivers of malignancy, predict treatment response, and develop novel therapies. A lack of reproducibility when comparing identified genetic mutations with treatment response is challenging because a single genetic change does not reflect the cellular state of a cancer cell in its entirety, which is expressing a multitude of genes. Computational methods allow for the creation of mapping systems that may more accurately describe the cellular state and thereby predict treatment response. Objective: We used Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment response using patient-derived xenografts (PDX). Methods: RNA transcription abundance from medulloblastoma samples published by Cho et al. were used to create C2M2. This was accomplished by analyzing the distribution of transcriptional abundance for each gene across all samples in order to select the genes that display the most asymmetric and non-Gaussian behavior. This delineated a “context score” for each gene, emphasizing those over- and underexpressed, allowing for the creation of a unique signature to model cellular states. The medulloblastoma samples from Cho et al. were then plotted onto the map based upon their RNA transcriptional abundance signatures, creating clusters of similar cellular states. Likewise, RNA transcription abundance from 20 PDX samples, for which drug response was known, was then mapped. Results: C2M2 identified ten cellular states for medulloblastoma by which to define patient samples: SHH DNA repair, SHH glutamate signaling, SHH RNA repair, WNT, Photoreceptor and MYC (in which Group 3 medulloblastoma falls), Neuronal migration, Neuronal MAPK activation and Axonal (in which Group 4 medulloblastoma falls), and Homeobox activation. PDX samples for which drug response was known clustered similarly onto the map. Conclusion: C2M2 using RNA transcriptional abundance from medulloblastoma samples could be used to predict drug response. Citation Format: Huwate Yeerna, Benjamin Briggs, Jessica Rusert, Lukas Chavez, Jill Mesirov, Robert Wechsler-Reya, Pablo Tamayo. Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment response [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B21.
Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes
Authors: Marco Mazzotta, Marco Filetti, Mario Occhipinti, Daniele Marinelli, Stefano Scalera, Irene Terrenato, Francesca Sperati, Matteo Pallocca, Francesco Rizzo, Alain Gelibter, Andrea Botticelli, Giorgia Scafetta, Arianna Di Napoli, Eriseld Krasniqi, Laura Pizzuti, Maddalena Barba, Silvia Carpano, Patrizia Vici, Maurizio Fanciulli, Francesca De Nicola, Ludovica Ciuffreda, Frauke Goeman, Ruggero De Maria, Andrea Vecchione, Raffaele Giusti, Gennaro Ciliberto, Paolo Marchetti, Marcello Maugeri-Saccà
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice. Methods We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS). Results In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH mut /HR mut signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH mut /HR mut genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH mut /HR mut signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002). Conclusions Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.
p16/ki67 and E6/E7 mRNA Accuracy and Prognostic Value in Triaging HPV DNA-Positive Women
Authors: Paolo Giorgi Rossi, Francesca Carozzi, Guglielmo Ronco, Elena Allia, Simonetta Bisanzi, Anna Gillio-Tos, Laura De Marco, Raffaella Rizzolo, Daniela Gustinucci, Annarosa Del Mistro, Helena Frayle, Massimo Confortini, Anna Iossa, Elena Cesarini, Simonetta Bulletti, Basilio Passamonti, Silvia Gori, Laura Toniolo, Alessandra Barca, Laura Bonvicini, Pamela Mancuso, Francesco Venturelli, Maria Benevolo
Journal: JNCI Journal of the National Cancer Institute (2020)

The study presents cross-sectional accuracy of E6 and E7 (E6/E7) mRNA detection and p16/ki67 dual staining, alone or in combination with cytology and human papillomavirus (HPV)16/18 genotyping, as a triage test in HPV DNA-positive women and their impact on cervical intraepithelial neoplasia (CIN2+) overdiagnosis.
Abstract A75: Mithramycin evicts SWI/SNF from chromatin to induce epigenetic reprogramming in rhabdoid tumor
Authors: Maggie H. Chasse, Benjamin K. Johnson, Elissa A. Boguslawski, Katie M. Sorensen, Ian Beddows, Zachary Madaj, Gabrielle E. Foxa, Kristin J. Rybski, Susan M. Kitchen-Goosen, Bart O. Williams, Timothy J. Triche, Patrick J. Grohar
Journal: Cancer Research (2020)

Abstract The text of this abstract has not been printed at the request of the authors due to intellectual property matters. Citation Format: Maggie H. Chasse, Benjamin K. Johnson, Elissa A. Boguslawski, Katie M. Sorensen, Ian Beddows, Zachary Madaj, Gabrielle E. Foxa, Kristin J. Rybski, Susan M. Kitchen-Goosen, Bart O. Williams, Timothy J. Triche Jr., Patrick J. Grohar. Mithramycin evicts SWI/SNF from chromatin to induce epigenetic reprogramming in rhabdoid tumor [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A75.