tbuckley/cabot-search huggingface dataset:
Validation of the IPSET score for thrombosis in patients with prefibrotic myelofibrosis
Authors: Paola Guglielmelli, Alessandra Carobbio, Elisa Rumi, Valerio De Stefano, Lara Mannelli, Francesco Mannelli, Giada Rotunno, Giacomo Coltro, Silvia Betti, Chiara Cavalloni, Maria Chiara Finazzi, Juergen Thiele, Mario Cazzola, Alessandro Maria Vannucchi, Tiziano Barbui
Journal: Blood Cancer Journal (2020)

Pre-fibrotic myelofibrosis (pre-PMF) and essential thrombocythemia (ET) are characterized by similarly increased rate of thrombotic events, but no study specifically analyzed risk factors for thrombosis in pre-PMF. In a multicenter cohort of 382 pre-PMF patients collected in this study, the rate of arterial and venous thrombosis after diagnosis was 1.0 and 0.95% patients/year. Factors significantly associated with arterial thrombosis were age, leukocytosis, generic cardiovascular risk factors, JAK2V617F and high molecular risk mutations, while only history of previous thrombosis, particularly prior venous thrombosis, was predictive of venous events. The risk of total thromboses was accurately predicted by the the international prognostic score for thrombosis in essential thrombocythemia (IPSET) score, originally developed for ET, and corresponded to 0.67, 2.05, and 2.95% patients/year in the low-, intermediate-, and high-risk categories. IPSET was superior to both the conventional 2-tiered score and the revised IPSET in this cohort of pre-PMF patients. We conclude that IPSET score can be conveniently used for thrombosis risk stratification in patients with pre-PMF and might represent the basis for individualized management aimed at reducing the increased risk of major cardiovascular events. Further refinement of the IPSET score in pre-PMF might be pursued by additional, prospective studies evaluating the inclusion of leukocytosis and/or adverse mutational profile as novel variables.
Oxaliplatin, Irinotecan, Bevacizumab followed by Docetaxel, Bevacizumab in Inoperable Gastric Cancer. A Multicenter Phase II Trial (AGMT Gastric-3) of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT)
Authors: E. Wöll, F. Keil, J. Thaler, B. Gruenberger, M. Hejna, W. Eisterer, M.A. Fridrik, F. Romeder, R. Greil
Journal: Annals of Oncology (2012)
Using high-resolution magic angle spinning magnetic resonance spectroscopy to characterize the metabolomic profile of fat-poor angiomyolipoma and renal cell carcinoma.
Authors: Melissa Jessica Huynh, Andrew Gusev, Francesco Palmas, Lindsey Vandergrift, Chin-Lee Wu, Leo Cheng, Adam S. Feldman
Journal: Journal of Clinical Oncology (2020)

711 Background: Fat-poor angiomyolipoma (AML) can be difficult to differentiate from renal cell carcinoma (RCC) radiographically and may lead to biopsy or unnecessary intervention. In vivoplatforms with the ability to identify tumor histology based on metabolic profiles may avoid unnecessary procedures &amp; their complications. The metabolomics of AML have not been characterized, &amp; research into this area may provide targetable molecules for large AMLs. In this study, we investigate the metabolomic profile of AMLs compared to clear cell RCC (ccRCC) using high resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Methods: Tissue samples were obtained from radical or partial nephrectomy specimens that were fresh frozen &amp; stored at -80ºC. Tissue HRMAS MRS was performed by a Bruker AVANCE spectrometer. Metabolomic profiles of RCC &amp; adjacent benign renal tissue were compared, and false discovery rates (FDR) accounted for multiple testing. Regions of interest (ROI) with FDR &lt;0.05 were considered potential predictors of ccRCC rather than AML. The Wilcoxon rank sum test was used to compare median MRS relative intensities for candidate predictors. Logistic regression was used to determine odds ratios for risk of malignancy based on abundance of each metabolite. Results: There were 16 ccRCC samples &amp; 7 AML specimens. Candidate predictors of malignancy rather than AML based on FDR p-values include histidine, phenylalanine, phosphocholine, serine, alanine, glutamate, glutathione, glycerophosphocholine, &amp; glutamine. While an abundance of these metabolites is associated with higher risk of malignancy, the odds ratio was particularly high in the 3.5-3.49 ppm spectral region (OR 2.99x10 6 , 95% CI 3.27, 2.73x10 12 , p=0.033)in ccRCC samples. Conclusions: HRMAS MRS identified metabolites that may help differentiate fat-poor AML from ccRCC. In particular, metabolites in the 3.5-3.49 ppm spectral region increased the risk of harboring RCC. Our findings may contribute to future in vivostudies to help identify which patients require intervention for malignancy &amp; which may be observed for benign AML without requiring biopsy.
A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled GDC-0214, a JAK1 Inhibitor, as Single- and Multiple-Ascending Doses in Healthy Volunteers
Authors: Ryan Owen, Joshua Galanter, Rui Zhu, Fang Cai, Jennifer Tom, Chris Wynne, Matthew Durk, Liuxi Chen, Jane Kenny, Gaohong She, Shweta Vadhavkar, Olivia Hwang, Hubert Chen
Journal: Journal of Allergy and Clinical Immunology (2020)
Nfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in Zebrafish
Authors: Felix Gunawan, Alessandra Gentile, Sébastien Gauvrit, Didier Y.R. Stainier, Anabela Bensimon-Brito
Journal: Circulation Research (2020)

The transcription factor NFATC1 (nuclear factor of activated T-cell 1) has been implicated in cardiac valve formation in humans and mice, but we know little about the underlying mechanisms. To gain mechanistic understanding of cardiac valve formation at single-cell resolution and insights into the role of NFATC1 in this process, we used the zebrafish model as it offers unique attributes for live imaging and facile genetics.To understand the role of Nfatc1 in cardiac valve formation.Using the zebrafish atrioventricular valve, we focus on the valve interstitial cells (VICs), which confer biomechanical strength to the cardiac valve leaflets. We find that initially atrioventricular endocardial cells migrate collectively into the cardiac jelly to form a bilayered structure; subsequently, the cells that led this migration invade the ECM (extracellular matrix) between the 2 endocardial cell monolayers, undergo endothelial-to-mesenchymal transition as marked by loss of intercellular adhesion, and differentiate into VICs. These cells proliferate and are joined by a few neural crest-derived cells. VIC expansion and a switch from a promigratory to an elastic ECM drive valve leaflet elongation. Functional analysis of Nfatc1 reveals its requirement during VIC development. Zebrafish nfatc1 mutants form significantly fewer VICs due to reduced proliferation and impaired recruitment of endocardial and neural crest cells during the early stages of VIC development. With high-speed microscopy and echocardiography, we show that reduced VIC formation correlates with valvular dysfunction and severe retrograde blood flow that persist into adulthood. Analysis of downstream effectors reveals that Nfatc1 promotes the expression of twist1b-a well-known regulator of epithelial-to-mesenchymal transition.Our study sheds light on the function of Nfatc1 in zebrafish cardiac valve development and reveals its role in VIC formation. It also further establishes the zebrafish as a powerful model to carry out longitudinal studies of valve formation and function.
Combination HDACi and mTOR inhibitor therapy in poor-risk de novo and refractory elderly patients with AML.
Authors: Vijay Krishna Sandilya, Vikas Ghai, Kamal Sharma, Kamal Kant Singh Abbi, Elliot E Epner
Journal: Journal of Clinical Oncology (2013)

e18012 Background: Valproic acid (VPA, 2-propylpentanoic acid) is a histone deacetylase inhibitors (HDACi), which has in vitro activity against Acute Myeloid Leukemia (AML) blasts. HDACi produce epigenetic modifications, and may have antineoplastic effects in AML by activating transcriptional silenced genes. The mammalian target of rapamycin (mTOR) pathways constitutive activation has been involved in the pathogenesis of various cancers, including AML. We present a series of two cases of poor risk de novo and refractory elderly AML patients treated with a combination of HDACi VPA and mTOR inhibitor sirolimus (S). Methods: This is a retrospective chart review garnered data on two patients with de novo AML and refractory AML who were treated with a combination therapy of VPA 500 mg three times a day with sirolimus 1 mg by mouth daily. Patients continued to receive treatment until disease progression. Results: Patient 1 achieved transfusion independence and a 6 month CR with ECOG PS 1 without hospitalizations. Repeat BM demonstrated no morphologic or immunophenotypic evidence of AML. Persistent disease was still detectable by FISH. Patient 2 was started on the regimen after persistent disease was detected by day 14 bone marrow, post standard 7 + 3 induction. Repeat bone marrow after 23 days of treatment with VPA and Sirolimus showed no immunophenotypic, morphological or cytogenetic evidence of AML. The patient remained in remission for 9 months on therapy with normal blood counts. Conclusions: We postulate that the use of VPA with sirolimus, is an active combination therapy for elderly, poor risk AML patients who may not otherwise tolerate intensive chemotherapy. The mechanism of action may involve activation of the mTORC2 pathway by HDAC1. Given our observations, further studies are warranted to better define the activity of this or similar combination therapies in elderly AML patients. [Table: see text]
Design of fish breakapart probes for the diagnosis of childhood sarcomas: Validation on cell lines and paraffin embedded samples
Authors: Sandra Rodríguez-Perales, Ma Carmen Martin, Blanca Fernandez, Javier Benitez, Juan C. Cigudosa
Journal: Cancer Research (2004)

1693  Childhood soft tissue sarcomas account for approximately 10% of all childhood cancers. About half of all children sarcomas are rhabdomyosarcoma (RMS), which arises from skeletal muscle. The other soft tissue sarcomas of childhood include a wide range of different histologies as Ewing sarcoma (ES)/ peripheral neuroectodermal tumours (PNET), synovial sarcoma (SS), among others. These tumors fall into a category referred to by pathologists as the “small round blue cell tumor” (SRBCT) because the homogeneous, densely cellular appearance. Treatment modalities and prognosis vary significantly among the various SRBCT subtypes so arriving at the correct diagnosis is of critical importance. Most of these tumors contain chromosome rearrangements that are diagnostic and truly specific of different SRBCT: e.g., the alveolar subtype of RMS (ARMS) is characterized by the presence of a reciprocal translocation t(2;13)(q35;q14) and the variant t(1;13)(p36;q14), that involve the genes PAX3, PAX7 and FKHR. Most of ES/PNET cases harbor the t(11;22)(q24;q12) translocation that fusion EWS and FLI1 genes. And finally, SS is characterized by the t(X;18) translocation that fuses SS18 gene with either SSX1 or SSX2 genes. Traditional detection methods as immunohistochemistry and RT-PCR have been generally used in the diagnosis, however they show some limitations. For this reason, we have improved a method of Fluorescence in situ hybridisation (FISH), which permits evaluation of chromosomal rearragements in archival tissue tumors and keeps the architectural organization of the tissue. We have design gene specific breakapart probes for FKHR and EWS genes. These probes detect any rearrangement affecting the genes, both the most frequent and all the variant translocations. Traditional fusion probes were designed for the differential diagnosis of SSX1/SS18 and SSX2/SS18 fusion genes. Our probes derived from BACs, yielded strong and distinctive signals, that are easily seen in the paraffin embedded tissue. For validation of the probes, we have used two cell lines derived from RMS and ES cases. The cell lines are: RH-30, RMZ-RC2, A-673 and CME. Prior to validation we perform a complete molecular cytogenetic study of all these cell lines. We could detect the chromosomal translocation specific of these children sarcomas. After establishing the specificity of the probes, we evaluated a series of RMS, ES and SS cases.
Chronic urticaria in children can be controlled effectively with updosing second-generation antihistamines
Authors: Sofianne Gabrielli, Michelle Le, Elena Netchiporouk, Barbara Miedzybrodzki, Sharon Baum, Shoshana Greenberger, Petra Staubach-Renz, Moshe Ben-Shoshan
Journal: Journal of the American Academy of Dermatology (2020)
An Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury
Authors: Tariq A Bhat, Suresh G Kalathil, Paul N Bogner, Benjamin C Blount, Maciej L Goniewicz, Yasmin M Thanavala
Journal: New England Journal of Medicine (2020)

An Animal Model of EVALI In this study, investigators developed a mouse model of e-cigarette, or vaping, product use–associated lung injury. They showed that in these mice, vitamin E acetate induce...
IL‐1β prevents ILC2 expansion, type 2 cytokine secretion, and mucus metaplasia in response to early‐life rhinovirus infection in mice
Authors: Mingyuan Han, Tomoko Ishikawa, Jennifer R. Bermick, Charu Rajput, Jing Lei, Adam M. Goldsmith, Caitlin R. Jarman, Julie Lee, J. Kelley Bentley, Marc B. Hershenson
Journal: Allergy (2020)

Abstract Background Early‐life wheezing‐associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6‐day‐old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL‐13‐producing type 2 innate lymphoid cells (ILC2s) and dependent on IL‐25 and IL‐33. We examined regulation of this asthma‐like phenotype by IL‐1β. Methods Six‐day‐old wild‐type or NRLP3−/− mice were inoculated with sham or RV‐A1B. Selected mice were treated with IL‐1 receptor antagonist (IL‐1RA), anti‐IL‐1β, or recombinant IL‐1β. Results Rhinovirus infection induced Il25 , Il33 , Il4 , Il5 , Il13 , muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro‐IL‐1β and NLRP3 as well as cleavage of caspase‐1 and pro‐IL‐1β, indicating inflammasome priming and activation. Lung macrophages were a major source of IL‐1β. Inhibition of IL‐1β signaling with IL‐1RA, anti‐IL‐1β, or NLRP3 KO increased RV‐induced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing IL‐17 mRNA expression. Treatment with IL‐1β had the opposite effect, decreasing IL‐25, IL‐33, and mucous metaplasia while increasing IL‐17 expression. IL‐1β and IL‐17 each suppressed Il25 , Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RV‐infected 6‐day‐old mice showed reduced IL‐1β mRNA and protein expression compared to mature mice. Conclusion Macrophage IL‐1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL‐1β production in immature animals provides a mechanism permitting asthma development after early‐life viral infection.
FDG and PSMA PET in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Katherine A. Zukotynski, Hossein Jadvar, Steve Y. Cho, Chun Ki Kim, Kathryn Cline, Urban Emmenegger, Sebastien J. Hotte, Gregory Russell Pond, Eric Winquist
Journal: Journal of Clinical Oncology (2020)

23 Background: We hypothesized 18 F-DCFPyL (PSMA-based tracer) and/ or 18 F-FDG (glucose metabolism-based tracer) PET/CT might provide different/complementary molecular imaging information in men with mCRPC treated with abiraterone (A) or enzalutamide (E). Methods: In this prospective cohort study (MISTER trial) mCRPC patients (pts) had conventional imaging and both PSMA and FDG PET/CT prior to standard treatment with A or E, repeated after ~10 weeks on treatment. The main objective was to compare changes in PET/CT findings with conventional imaging. Median of PET maximum standardized uptake value (SUVmax) was measured across all PET avid disease sites and change in SUVmax was evaluated in the 5 hottest sites per patient. Review of PET/CT was performed by 3 experts based on consensus. Results: 36 men were enrolled between 2/2017-12/2018, of whom 28 had treatment and followup imaging. To date, 13 cases have been reviewed: mean age 71.2 years, 7 (53.9%) were ECOG=0, median duration since diagnosis of initial cancer 7.5 months and 8 (61.5%) were stage II/III. PSMA detected more skeletal metastases, positive nodes and non-skeletal, non-nodal metastases in 5/5/3 (39%/39%/23%) men, while FDG detected more non-skeletal, non-nodal metastases in 1 man. Following treatment, new lesions were seen in 3 men on both PSMA and FDG, 3 with PSMA only, and 1 with FDG only. 12 men had baseline FDG-avid disease with median SUVmax 6.5 pre-treatment and 3.8 following therapy (all men had lower SUVmax post-treatment). All 13 men had PSMA-avid disease with median SUVmax 17.6 at baseline and 18.7 post-therapy. Following treatment, 8/12 men (67%) had SUV declines ≥30% (2 had new lesions), 4 had declines of 0-30% (2 had new lesions) using FDG; at followup, 1/13 men had PSMA SUVmax declines ≥30% or more, 6 had declines of 0-30% (2 had new lesions), 5 had SUV increases of 0-30% (4 had new lesions) and 1 had &gt;30% increase. Conclusions: In early analyses, PSMA identified more disease burden in mCRPC pts and was more avid than FDG. SUVmax for FDG declined following treatment in all men, while PSMA changes were heterogeneous. Potential prognostic value of early PSMA and FDG imaging changes on clinical outcomes will be correlated with conventional imaging along with review of remaining cases. Clinical trial information: NCT02813226.
Comparison of micro-ultrasound and multiparametric MRI imaging for prostate cancer: A multicenter prospective analysis.
Authors: Laurence Klotz, Giovanni Lughezzani, Andrrea Sanchez, Frederic Staerman, Hannes Cash, Richard Gaston, Rafael Sanchez-Salas, Eric A. Klein, Gregg Eure
Journal: Journal of Clinical Oncology (2020)

296 Background: This study aims to compare the sensitivity, specificity, NPV and PPV of mpMRI with the novel high-resolution micro-ultrasound imaging modality. This approach offers the benefits of simplicity, a single intervention for imaging and biopsy, leveraging the low cost of ultrasound. Micro-ultrasound may be used to image suspicious lesions and target biopsies in real-time with or without additional MRI-based targets. Methods: Data from 9 sites was aggregated, totaling 866 subjects presenting for ExactVu micro-ultrasound guided biopsy with available mpMRI studies. Samples in all subjects were taken from mpMRI targets and micro-ultrasound targets, with up to 12 systematic samples filled in. Various strategies were used for mpMRI target sampling including cognitive fusion with micro-ultrasound, separate software-fusion systems, and software-fusion using the micro-ultrasound FusionVu system. Clinically significant cancer was considered any Gleason Sum &gt; 6 and targeted samples were taken for PI-RADS &gt; 2 or PRI-MUS 1 &gt; 2 lesions. Results: Overall, 39% of all biopsy cases were positive for clinically significant PCa. mpMRI demonstrated 89% sensitivity and NPV of 77%. Compared to mpMRI, micro-ultrasound sensitivity (95%) and NPV (87%) were higher. Micro-ultrasound was less specific (21% vs 23% for mpMRI) with similar PPV (44% vs 43%). The aggregate effect demonstrates higher sensitivity for csPCa with micro-ultrasound compared to mpMRI (p&lt;0.01). Conclusions: Micro-ultrasound is an attractive option for screening and targeted biopsy. Sensitivity and NPV appear superior to MRI, but specificity is mildly reduced. Further larger-scale studies are required for validation of these findings. References: Ghai, S. et al., “Assessing Cancer Risk in Novel 29 MHz Micro-Ultrasound Images of the Prostate”, Journal of Urology, 2016 Aug;196(2):562-9. Clinical trial information: NCT03938376.
IND candidate EPI-7386 as an N-terminal domain androgen receptor inhibitor in development for the treatment of prostate cancer.
Authors: Ronan Le Moigne, C. Adriana Banuelos, Nasrin R. Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J. Andersen, Alessandra Cesano, Marianne Sadar, Han-Jie Zhou, Peter Virsik
Journal: Journal of Clinical Oncology (2020)

142 Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively active AR splice variants lacking the LBD (e.g. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. In a phase I trial, the first-generation AR NTD inhibitor (aniten) EPI-002, demonstrated minor PSA declines in mCRPC patients. The efficacy and safety profile of second generation aniten IND-candidate EPI-7386 will be presented. Methods: Novel aniten chemical structures were developed to increase molecule potency using a wide variety of CRPC models. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. IND-enabling studies further support the compounds’ safety profile. Results: EPI-7386 demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human hepatocytes and across animal species. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to induce tumor regression in CRPC xenografts and show superiority to enzalutamide (ENZ) in ENZ resistant models. In addition, the combination of ENZ with EPI-7386 demonstrated a more robust antitumor response. IND-enabling studies demonstrate a safe and well-tolerated profile supporting an IND filing in 1Q 2020. Pharmacodynamic markers specific to anitens will be presented, in addition to early clinical development plans. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-002. It demonstrated potential as a single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of aniten will be discussed.
Real-world Evidence of Improved Patient Outcomes With Reslizumab in Non-exacerbating Patients With Severe Eosinophilic Asthma (SEA): A Subgroup Analysis
Authors: Stephen Peters, Michael Wechsler, Bradley Chipps, Tanisha Hill, Rinat Ariely, Michael Depietro, Emi Terasawa, Darren Thomason, Reynold Panettieri
Journal: Journal of Allergy and Clinical Immunology (2020)