tbuckley/cabot-search huggingface dataset:
A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients
Authors: F. Robert, C. Verschraegen, H. Hurwitz, H. Uronis, R. Advani, A. Chen, P. Taverna, M. Wollman, J. Fox, G. Michelson
Journal: Journal of Clinical Oncology (2009)

2536 Background: Aurora Kinases are a family of serine/threonine kinases (Aurora Kinases (AK) A, B, and C) critical for mitosis. Elevated AKs expression occurs in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors; in a subset of these tumors the AURKA locus (20q13) is amplified. SNS-314 is a selective pan-AK inhibitor with low nanomolar IC50s. Methods: Study design is 3+3 phase 1 dose escalation by modified Fibonacci. Patients (pts) with advanced solid tumors received SNS-314 by 3 hour infusion qweek X 3 (28 day cycle). Primary endpoints: safety, tolerability, and DLT assessment. Secondary endpoints: MTD, pharmacokinetics (PK), pharmacodynamics, and antitumor activity. Pharmacodynamic endpoint was inhibition of Histone H3 phosphorylation (pHH3) evaluated by immunohistochemistry of skin punch biopsies taken pre- and 2 hours post-infusion. Results: Thirty-two pts (16M/16F; median age = 58.5 years) were enrolled into 8 cohorts: dose range 30–1800 mg/m 2 . Median cycles received =2. SNS-314 was generally well tolerated with Grade 1–2 toxicities ≥ 15% incidence: nausea (31%), fatigue (28%), vomiting, constipation, and pain (16% each), and no Grade 3+ toxicities of ≥ 15% incidence. A DLT of Grade 3 neutropenia preventing administration of all 3 doses was observed at 1440 mg/m 2 . Plasma PK were dose proportional for exposure with no accumulation of SNS-314 following weekly administration. Clearance was moderate (5.65 L/hr/m 2 , CV 39.4%); Vss approximated total body water (21.5 L/m 2 , CV 78.1%); terminal half-life was 10.4 hours (CV 66.8%). Six patients had stable disease as their best response. Inhibition of pHH3 by SNS-314 was observed in skin biopsies of patients treated at doses of 240 mg/m 2 and greater. Conclusions: SNS-314 is a novel inhibitor of AKs A, B, and C. The compound has been generally well tolerated; MTD was not established. No objective responses were observed. Pharmacodynamic activity was demonstrated by inhibition of pHH3. [Table: see text]
THU0022 Kir3Dl1 (nkb1) and cd94 expression on peripheral blood t cells, nk cells and nkt cells in behcet’s disease
Authors: G Saruhan Direskeneli, FA Uyar, A Cefle, S Celebi Onder, M Inanc, L Ocal, A Gul
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Behcet’s disease (BD) is strongly associated with HLA-B51. However, the role of HLA-B51 in the pathogenesis still remains to be elucidated. We have recently identified a weak association of HLA-B*2702 with BD. HLA-B51 and B*2702 shares one of the 5 Bw4 motifs at positions 77–83, which interacts with a group of recently described receptors on mainly NK cells, but also CD8<sup>+</sup> and gamma-delta T cells. Interaction of HLA-B molecules with one of these receptors, killer immunoglobulin-like receptor (KIR) on NK, NKT, CD8<sup>+</sup> and/or gamma/delta T cells may be one of the pathogenic mechanisms involved in BD. <h3>Objectives</h3> We aimed to investigate the KIR3DL1 and CD94 (a C-type lectin receptor which mainly interacts with HLA-E) expression in BD. <h3>Methods</h3> The study group consisted of 51 patients, who fulfil the International Study Group Criteria, and 32 HLA-Bw4 motif matched healthy controls. All patients and controls were already HLA-typed, and they were selected and grouped according to the presence and number of the shared Bw4 epitope. All of the patients were receiving treatment and their disease activity was under control. Expression patterns of CD3, CD16, CD56, CD45, CD14, KIR3DL1 (NKB1) and CD94 in peripheral blood leukocytes were determined with fluorescent-labelled monoclonal antibodies using flow cytometry. <h3>Results</h3> The percentage of CD3<sup>+</sup> cells was found to be increased in BD patients, but there was no significant difference in NK (CD56<sup>+</sup>/CD16<sup>+</sup>, CD3-/CD56<sup>+</sup>) and NKT (CD3<sup>+</sup>/CD56<sup>+</sup>) cells between BD patients and controls. The distribution of KIR3DL1 receptor did not show any significant difference in patients, however we observed a significant increase of CD94 expression in T cells, NK and NKT cells. Subgroup analysis in patients carrying 1, 2 or no copies of the shared Bw4 motif also did not reveal any effect on the expression of KIR3DL1 and CD94. <h3>Conclusion</h3> We did not observe any difference in the expression of KIR3DL1 receptors in this group of BD patients compared with healthy HLA-Bw4 motif matched controls. Increased CD94 expression in peripheral blood T cells, NK and NKT cells of BD patients needs to be confirmed and analysed further. This study was supported by the Research Fund of the University of Istanbul (1076).
Artificial intelligence in medical imaging: switching from radiographic pathological data to clinically meaningful endpoints
Authors: Ohad Oren, Bernard J Gersh, Deepak L Bhatt
Journal: The Lancet Digital Health (2020)

Artificial intelligence (AI) is a disruptive technology that involves the use of computerised algorithms to dissect complicated data. Among the most promising clinical applications of AI is diagnostic imaging, and mounting attention is being directed at establishing and fine-tuning its performance to facilitate detection and quantification of a wide array of clinical conditions. Investigations leveraging computer-aided diagnostics have shown excellent accuracy, sensitivity, and specificity for the detection of small radiographic abnormalities, with the potential to improve public health. However, outcome assessment in AI imaging studies is commonly defined by lesion detection while ignoring the type and biological aggressiveness of a lesion, which might create a skewed representation of AI's performance. Moreover, the use of non-patient-focused radiographic and pathological endpoints might enhance the estimated sensitivity at the expense of increasing false positives and possible overdiagnosis as a result of identifying minor changes that might reflect subclinical or indolent disease. We argue for refinement of AI imaging studies via consistent selection of clinically meaningful endpoints such as survival, symptoms, and need for treatment.
Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice
Authors: Yuqing Liu, Xiaoqi Wang, Yongping Zhu, Mingfeng Zhang, Ubaydah Nasri, Sharne S. Sun, Stephen J. Forman, Arthur D. Riggs, Xi Zhang, Defu Zeng
Journal: Journal of Clinical Investigation (2020)

Clinical trials are currently testing whether induction of haploidentical mixed chimerism (Haplo-MC) induces organ transplantation tolerance. Whether Haplo-MC can be used to treat established autoimmune diseases remains unknown. Here, we show that established autoimmunity in euthymic and adult-thymectomized NOD (H-2g7) mice was cured by induction of Haplo-MC under a non-myeloablative anti-thymocyte globulin-based conditioning regimen and infusion of CD4+ T cell-depleted hematopoietic graft from H-2b/g7 F1 donors that expressed autoimmune-resistant H-2b or from H-2s/g7 F1 donors that expressed autoimmune-susceptible H-2s. The cure was associated with enhanced thymic negative selection, increased thymic Treg (tTreg) production, and anergy or exhaustion of residual host-type autoreactive T cells in the periphery. The peripheral tolerance was accompanied by expansion of donor- and host-type CD62L-Helios+ tTregs as well as host-type Helios-Nrp1+ peripheral Tregs (pTregs) and PD-L1hi plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type PD-L1hi pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and Helios-Nrp1+ pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-MHC+ donor-type DCs, PD-L1hi host-type DCs, and the generation and persistence of donor- and host-type tTregs and pTregs.
Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study
Authors: Giacomo Grasselli, Tommaso Tonetti, Alessandro Protti, Thomas Langer, Massimo Girardis, Giacomo Bellani, John Laffey, Gianpaolo Carrafiello, Luca Carsana, Chiara Rizzuto, Alberto Zanella, Vittorio Scaravilli, Giacinto Pizzilli, Domenico Luca Grieco, Letizia Di Meglio, Gennaro de Pascale, Ezio Lanza, Francesco Monteduro, Maurizio Zompatori, Claudia Filippini, Franco Locatelli, Maurizio Cecconi, Roberto Fumagalli, Stefano Nava, Jean-Louis Vincent, Massimo Antonelli, Arthur S Slutsky, Antonio Pesenti, V Marco Ranieri, Alfredo Lissoni, Nicola Rossi, Amedeo Guzzardella, Carlo Valsecchi, Fabiana Madotto, Francesca Bevilacqua, Marco Di Laudo, Lorenzo Querci, Carmen Seccafico
Journal: The Lancet Respiratory Medicine (2020)
A third Notch in colorectal cancer progression and metastasis
Authors: Ute Koch, Freddy Radtke
Journal: The Journal of Experimental Medicine (2020)

In this issue of JEM, Varga et al. (https://doi.org/10.1084/jem.20191515) describe a mouse model of invasive and metastatic colorectal cancer (CRC) closely resembling the human consensus molecular subtype (CMS) 4 associated with the poorest overall survival of the four CMSs. Transcriptomic and bioinformatic analysis combined with pharmacological and genetic studies identified Notch3 as a promoter of tumor progression and metastasis. NOTCH3 expression was up-regulated in CMS4 CRC patients and associated with tumor staging, lymph node and distant metastasis. These findings feature NOTCH3 as putative therapeutic target for advanced CMS4 CRC patients.
FRI0015 Azathioprine withdrawal in rheumatoid arthritis patients. role of tpmt genetic polymorphisms
Authors: H Corominas, M Domènech, A Laiz, M Moreno, C Geli, C Diaz, G Vázquez, M Baiget
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Dose-dependent Azathioprine´s bone marrow toxicity is widely accepted, although identification of the genetic polimorphysm of the Thiopurine methyltransferase (TPMT) is being recently recognised. <h3>Objectives</h3> The aim of the study was to investigate, if the appearance of drug related side effects, such as haematologic toxicity was due to the presence of allelic variants of the TPMT gene. <h3>Methods</h3> 111 RA patients DNA´s from WBC were amplified by PCR. Digestion with enzymes (MwoI and Acc) were performed, to identify the different allelic variants of the TPMT gene. MwoI digestion of the 284 bp PCR product resulted in fragments that either remained intact (mutant allele A460) or were cut in two segments of 267 bp and 17 bp (wild type allele G460A). AccI restriction site was present when the G719 mutation existed, the PCR products containing this mutation were cleaved (207 bp and 86 bp fragments) when digested with AccI, while the wild type fragments (A719) were not digested. Results were compared with 105 DNA samples from healthy donors. X2 tests on genotype frequencies and p &lt; 0.05 was statistically significant. <h3>Results</h3> 9.5% of healthy controls and 7.2% RA patients were heterozygous for a mutant allele of the TPMT gene. The most frequent variant in both groups was the TPMT 3A (G460A, A719G). Within the 111 RA, 40 of them had followed Aza therapy. 8 of them were still following this therapy, and 32 had to withdrawal Azathioprine therapy due to non response (n = 27) or adverse side effects (n = 5): These last 5 patients were homozygous for the Wild type TPMT allele. <h3>Conclusion</h3> TPMT genotype is to identify patients at risk of severe bone marrow toxicity if treated with Aza, Our study reveals that, severe side effects due to Azathioprine cannot be explained by the presence of these two mutant alleles. <h3>References</h3> Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LHJ, van de Putte LBA, Boeermooms A. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:142–5 Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV Evans WE. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997;126:608–14
Effect of insulin-like growth factor 1 receptor inhibitor on sensitization of head and neck cancer cells to cetuximab and methotrexate
Authors: H. Hatakeyama, J. Parker, D. Wheeler, P. Harari, S. Levy, C. H. Chung
Journal: Journal of Clinical Oncology (2009)

6079 Background: Insulin-like growth factor 1 receptor (IGF1R) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and IGF1R inhibitors have been shown to modulate sensitivity to selected chemotherapeutic agents and radiation. The combination effects of an IGF1R inhibitor, MK-0646, with cetuximab or cytotoxic agents that are commonly used in the treatment of recurrent and/or metastatic HNSCC were examined in cetuximab resistant and sensitive HNSCC cell lines. Methods: The cell lines, SCC1 and its cetuximab-resistant clone 1Cc8, were treated with MK-0646, cetuximab or methotrexate, and a combination of MK-0646 and each anti-cancer drug (MK-0646 was supplied by Merck &amp; Co., Inc.). The effect of treatments on cell proliferation and anti-tumor activity was determined using MTS assay in vitro and in vivo using mouse xenografts generated from the cell lines. Overall changes in the gene and protein expressions with the treatments were determined by DNA microarrays and western blots. Results: The IGF1R inhibitor, MK-0646, showed high-sensitivity in vitro xenograft model in SCC1 as monotherapy and increased sensitivity to cetuximab in SCC1 and to methotrexate in 1Cc8 in combination. However, MK-0646 did not inhibit cell proliferation in vitro and in vivo in 1Cc8. The gene expression array and western blot analyses showed that MK-0646 decreased expression of AKT and dihydrofolate reductase (DHFR), a target of methotrexate. Increased expressions of AKT and DHFR have been shown to associate with cetuximab and methotrexate resistance as well as radiation resistance. Conclusions: The development of tolerance in response to the IGF1R inhibitor and cetuximab is common. Whereas IGF1R inhibitors may have little therapeutic impact in cetuximab resistant, the IGF1R inhibitor may modulate response to selected chemotherapeutic agents and to radiation. The IGF1R inhibitor appears to enhance cetuximab and methotrexate response, and modulates genes associated with radiation resistance thereby providing alternative regimens for recurrent and refractory HNSCC patients who have developed resistance to initial therapies. No significant financial relationships to disclose.
COVID-19 and its impact on endoscopy services: what is the threshold for missed malignant diagnosis?
Authors: Tony He, Michael B MacIsaac, Simon J Hume, Alexander J Thompson, Julien D Schulberg
Journal: Gut (2020)

We read the study by Rutter et al 1 with interest. The substantial decrease in the cancer detection rate in the UK as a consequence of a reduction in endoscopy activity during the COVID-19 era is alarming. Early in the lockdown, UK endoscopy activity dropped to as low as 5% of pre-COVID levels, with activity only increasing to 20% after 10 weeks. More selective screening did significantly increase the per-procedure cancer detection rate (pre-COVID 1.91%; COVID-19 impacted 6.61%; p<0.001); however, despite this, endoscopic cancer detection reduced by 58% overall, with a concerning 72% detection reduction for colorectal cancer. Similarly, in the USA, a recent report found a 50% reduction in colorectal diagnosis as a result of the pandemic.2

COVID-19 remains an ongoing worldwide pandemic. Gastrointestinal (GI) endoscopy is considered an aerosol-generating procedure for SARS-CoV-2 transmission.3 There remain limited data to provide insight into creating a safe model for rationing …
Modulation of gut microbiota in healthy rats after exposure to nutritional supplements
Authors: Mirna Čoklo, Dina Rešetar Maslov, Sandra Kraljević Pavelić
Journal: Gut Microbes (2020)

Introduction Rats are experimental animals, frequently used as model organisms in the biomedical studies, and increasingly used to study the gut microbiota. Specifically, the aim of latter studies is either the elucidation of relationship between intestinal dysbiosis and diseases or the determination of nutrients or pharmaceutical agents which can cause the modulation in the presence or abundance of gut microbiota.Aim Herein, the research studies conducted on the gut microbiota of healthy rats are presented in a summarized and concise overview. The focus is on studies aimed to reveal the shifts in microbial composition and functional changes after exposure to various types of nutritional supplements.Methods We performed the search of PubMed database using the term "rat gut microbiome microbiota" and examined studies aimed to assess the composition of gut microbiota in physiological homeostasis as well as the effect of various nutritional supplements on the gut microbiota of healthy rats.
SARS–CoV-2–specific T cell responses and correlations with COVID-19 patient predisposition
Authors: Arne Sattler, Stefan Angermair, Helena Stockmann, Katrin Moira Heim, Dmytro Khadzhynov, Sascha Treskatsch, Fabian Halleck, Martin E. Kreis, Katja Kotsch
Journal: Journal of Clinical Investigation (2020)

Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.
Spiritual support of patients with advanced illness and associations with end-of-life care and quality of death
Authors: T. A. Balboni, M. E. Paulk, M. J. Balboni, E. D. Trice, A. A. Wright, A. C. Phelps, S. D. Block, H. G. Prigerson
Journal: Journal of Clinical Oncology (2009)

9514 Background: Little is known about whether spiritual support is associated with advanced cancer patients' medical care and quality of death (QoD) at the end of life (EoL). Methods: Coping with Cancer is an NCI/NIMH-funded, prospective, longitudinal, multi-institutional study of advanced, incurable cancer patients conducted from September 2002-August 2008. Analyses were based on 343 deceased patients who were interviewed at baseline and then followed until death a median of 117 days later. At baseline, spiritual support was assessed by (1) patient-rated support of spiritual needs by the medical system (eg, physicians, nurses, chaplains) scored from 0 (not at all) to 5 (completely supported) and (2) patient-reported receipt of hospital/clinic pastoral care services. Outcomes measured included medical care received in the last week of life (hospice; receipt of aggressive EoL care defined as ICU admission, resuscitation, ventilation or chemotherapy in the last week of life; and death in an acute care facility) and QoD. QoD assessments (possible 0–30, with increasing scores reflecting better QoD) were obtained by post-mortem interviews of a caregiver present in the patient's last week of life. Multivariable analyses examined (1) associations between spiritual support variables and EoL care outcomes, controlling for baseline confounds (eg, race, religiousness, patient EoL care preferences) and (2) associations between spiritual support variables and QoD with adjustment for confounds (eg, baseline quality of life, aggressive EoL care). Results: In adjusted analyses, greater medical system spiritual support was associated with increased receipt of hospice care [OR = 2.97 (1.24–7.11), p = .01], but not with receipt of aggressive EoL care or death in an acute care facility. Receipt of pastoral care services was not associated with any EoL care outcome. In adjusted analyses, spiritual support from the medical system and receipt of pastoral care services were significantly associated with better patient QoD (standardized β = 0.16, p = .009 and β = 0.20, p = .0005, respectively). Conclusions: Support of advanced cancer patients' spiritual needs by the medical care team is associated with increased receipt of hospice care and improved patient QoD. No significant financial relationships to disclose.
<i>Notes from the Field:</i> Universal Statewide Laboratory Testing for SARS-CoV-2 in Nursing Homes — West Virginia, April 21–May 8, 2020
Authors: Shannon M. McBee, Erica D. Thomasson, Melissa A. Scott, Christy L. Reed, Lauren Epstein, Amy Atkins, Catherine C. Slemp
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

This report describes how nursing homes in West Virginia used universal COVID-19 testing of residents and staff members to slow the spread of infections and prevent large outbreaks in this population at higher risk.