tbuckley/cabot-search huggingface dataset:
Discovery of Berberine that Targetedly Induces Autophagic Degradation of both BCR-ABL and BCR-ABL T315I through Recruiting LRSAM1 for Overcoming Imatinib Resistance
Authors: Zhao Yin, Guiping Huang, Chunming Gu, Yanjun Liu, Juhua Yang, Jia Fei
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Imatinib, the breakpoint cluster region protein (BCR)/Abelson murine leukemia viral oncogene homolog (ABL) inhibitor, is widely used to treat chronic myeloid leukemia (CML). However, imatinib resistance develops in many patients. Therefore, new drugs with improved therapeutic effects are urgently needed. Berberine (BBR) is a potent BCR-ABL inhibitor for imatinib-sensitive and -resistant CML. Experimental Design: Protein structure analysis and virtual screening were used to identify BBR targets in CML. Molecular docking analysis, surface plasmon resonance imaging, nuclear magnetic resonance assays, and thermoshift assays were performed to confirm the BBR target. The change in BCR-ABL protein expression after BBR treatment was assessed by Western blotting. The effects of BBR were assessed in vitro in cell lines, in vivo in mice, and in human CML bone marrow cells as a potential strategy to overcome imatinib resistance. Results: We discovered that BBR bound to the protein tyrosine kinase domain of BCR-ABL. BBR inhibited the activity of BCR-ABL and BCR-ABL with the T315I mutation, and it also degraded these proteins via the autophagic lysosome pathway by recruiting E3 ubiquitin-protein ligase LRSAM1. BBR inhibited the cell viability and colony formation of CML cells and prolonged survival in CML mouse models with imatinib sensitivity and resistance. Conclusions: The results show that BBR directly binds to and degrades BCR-ABL and BCR-ABL T315I via the autophagic lysosome pathway by recruiting LRSAM1. The use of BBR is a new strategy to improve the treatment of patients with CML with imatinib sensitivity or resistance. See related commentary by Elf, p. 3899
Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
Authors: Juan P. Arab, Daniel Cabrera, Tejasav S. Sehrawat, Nidhi Jalan-Sakrikar, Vikas K. Verma, Douglas Simonetto, Sheng Cao, Usman Yaqoob, Jonathan Leon, Mariela Freire, Jose I. Vargas, Thiago M. De Assuncao, Jung H. Kwon, Yi Guo, Enis Kostallari, Qing Cai, Tatiana Kisseleva, Youngman Oh, Marco Arrese, Robert C. Huebert, Vijay H. Shah
Journal: Journal of Hepatology (2020)
Abstract 14641: Computed Tomography Attenuation Values of Pericardial and Intrathoracic Adipose Tissue Are Novel Markers of Vulnerable Coronary Plaque
Authors: Aiko Sakamoto, Masae Uehara, Nobukazu Ishizaka, Jiro Ando, Issei Komuro
Journal: Circulation (2017)

Background: Ectopic fat deposition, such as pericardial adipose tissue (PAT) and intrathoracic adipose tissue (IAT), may mediate obesity-related cardiovascular disease. However, it remains unclear ...
Correction: Pure cystic groove pancreatitis: endosonographic appearance
Authors: Dario Ligresti, Matteo Tacelli, Michele Amata, Luca Barresi, Settimo Caruso, Ilaria Tarantino, Mario Traina
Journal: Endoscopy (2019)

Correction to: Pure cystic groove pancreatitis: endosonographic appearanceEndoscopy 2019; 51(08): E235-E236DOI: 10.1055/a-0889-7569
Outcome of older (≥70 years) APL patients frontline treated with or without arsenic trioxide—an International Collaborative Study
Authors: Sabine Kayser, Ramy Rahmé, David Martínez-Cuadrón, Gabriel Ghiaur, Xavier Thomas, Marta Sobas, Agnes Guerci-Bresler, Ana Garrido, Arnaud Pigneux, Cristina Gil, Emmanuel Raffoux, Mar Tormo, Norbert Vey, Javier de la Serna, Olga Salamero, Eva Lengfelder, Mark J. Levis, Pierre Fenaux, Miguel A. Sanz, Uwe Platzbecker, Richard F. Schlenk, Lionel Adès, Pau Montesinos
Journal: Leukemia (2020)

Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P < 0.001). The same held true when restricting the analysis according to the treatment period after the year 2000. OS of patients in CR1 was not different between ATO/ATRA ± CTX compared with CTX/ATRA (P = 0.20). High (>10 × 109/l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P < 0.001) compared with lower WBC in the CTX/ATRA group, but not in the ATO/ATRA ± CTX group (P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis.
Utilization of androgen deprivation therapy (ADT) and stereotactic body radiation therapy (SBRT) for localized prostate cancer (PC) in the United States (US).
Authors: Trevor Joseph Royce, Jeffrey M. Switchenko, Chao Zhang, Daniel Eidelberg Spratt, Ronald C. Chen, Ashesh B. Jani, Sagar Anil Patel
Journal: Journal of Clinical Oncology (2020)

370 Background: Randomized trials have demonstrated improved survival with the addition of ADT to conventionally fractionated radiotherapy (RT) for men with unfavorable intermediate risk (UIR) and high-risk (HR) prostate cancer (PC). The benefit of ADT with SBRT is unknown. The purpose of this study is to examine ADT utilization with SBRT in the US. Methods: Men &gt; 40 years old with localized PC treated with external beam RT for curative intent between 2004-2015 were analyzed from the National Cancer Database. Patients who received brachytherapy, surgery, or lacked ADT or risk stratification data were excluded. A total of 7,559 men treated with SBRT (≥5Gy/fraction; ≤5 fractions; dose ≥25Gy) versus 133,825 men treated with moderate or conventional RT (≤3Gy/fraction; dose ≥60Gy) were included. Patients were stratified by risk: low (LR), favorable intermediate (FIR), UIR, and HR using NCCN criteria. Differences between RT and SBRT were determined via Chi-square test. Results: Among all PC treated with RT, SBRT use increased from 2004 to 2015 across risk groups – overall: 0.9% to 10.3%; LR: 0.9% to 21.6%; FIR: 1.1% to 13.7%; UIR: 0.6% to 10.8%; HR: 0.8% to 2.8%; p &lt; 0.001. Among all PC treated with RT, ADT use declined from 2004 to 2015 for LR (22.8% to 5.5%), FIR (51.7% to 40.0%), UIR (53.4% to 49.5%), but not HR (78.9% to 84.2%); p &lt; 0.001. Patients with EBRT were more likely to receive ADT compared to those with SBRT across risk groups (Table). Conclusions: The majority of patients receiving SBRT for UIR and HR disease in the US do not receive concurrent ADT, despite national guideline recommendations and the lack of level 1 evidence to support this practice pattern. The omission of ADT may result in inferior oncologic outcomes, and randomized trials are needed to establish the safety of omitting ADT with SBRT for higher risk PC.[Table: see text]
Association of Dyslipidemia and Pulmonary Function in Asthmatic Children
Authors: Pakvirin Chanachon, Wiparat Manuyakorn, Wasu Kamchaisatian, Suwat Benjaponpitak, Watcharoot Kanchongkittiphon, Cherapat Sasisakulporn, Wanlapa Jotikasthira, Potjanee Kiewngam
Journal: Journal of Allergy and Clinical Immunology (2020)
Readthrough Errors Purge Deleterious Cryptic Sequences, Facilitating the Birth of Coding Sequences
Authors: Luke J Kosinski, Joanna Masel
Journal: Molecular Biology and Evolution (2020)

De novo protein-coding innovations sometimes emerge from ancestrally noncoding DNA, despite the expectation that translating random sequences is overwhelmingly likely to be deleterious. The "preadapting selection" hypothesis claims that emergence is facilitated by prior, low-level translation of noncoding sequences via molecular errors. It predicts that selection on polypeptides translated only in error is strong enough to matter and is strongest when erroneous expression is high. To test this hypothesis, we examined noncoding sequences located downstream of stop codons (i.e., those potentially translated by readthrough errors) in Saccharomyces cerevisiae genes. We identified a class of "fragile" proteins under strong selection to reduce readthrough, which are unlikely substrates for co-option. Among the remainder, sequences showing evidence of readthrough translation, as assessed by ribosome profiling, encoded C-terminal extensions with higher intrinsic structural disorder, supporting the preadapting selection hypothesis. The cryptic sequences beyond the stop codon, rather than spillover effects from the regular C-termini, are primarily responsible for the higher disorder. Results are robust to controlling for the fact that stronger selection also reduces the length of C-terminal extensions. These findings indicate that selection acts on 3' UTRs in Saccharomyces cerevisiae to purge potentially deleterious variants of cryptic polypeptides, acting more strongly in genes that experience more readthrough errors.
[18F]Fluciclovine-PET/MRI use in monitoring response to androgen deprivation therapy in men with prostate cancer following initial staging.
Authors: Samuel Joseph Galgano, Andrew Michael McDonald, Soroush Rais-Bahrami, Gagandeep Choudhary, Pradeep Bhambhvani, Jonathan McConathy
Journal: Journal of Clinical Oncology (2020)

216 Background: [ 18 F]Fluciclovine PET is clinically approved for detection of biochemically recurrent prostate cancer (PCa). However, its use for initial staging and treatment monitoring remains uncertain. No published data exists evaluating the use of fluciclovine-PET for monitoring response to androgen deprivation therapy. Thus, the purpose of this study is to evaluate the potential use of fluciclovine-PET in monitoring response to androgen deprivation therapy (ADT) during initial treatment of patients with newly diagnosed high risk PCa. Methods: A prospective study enrolled patients with high-risk PCa who had no imaging evidence of metastatic disease. All patients underwent a pretreatment fluciclovine-PET/MRI for primary staging, 6 weeks of ADT, and had a follow-up PET/MRI. All exams were interpreted by 3 nuclear medicine physicians. Identification of the primary intraprostatic lesion and nodal metastatic disease was performed with mean and maximum SUV of the MRI-defined primary prostatic lesions and lymph node metastases measured before and after ADT. Results: A total of 10 patients were enrolled. Gleason scores of their primary tumor were 3+4 (n = 2), 4+3 (n=2), 8 (n = 3), and 9 (n = 3). The average pretreatment serum PSA value was 33.04 ng/mL (range 2.83–76.5). The average serum PSA 6 weeks following initiation of ADT was 2.13 ng/mL (range 0.29–5.66). The primary intraprostatic lesion was accurately identified in all 10 patients and 7/10 patients demonstrated suspicious lymph nodes on the pretreatment PET/MRI. Following ADT, all 10 patients demonstrated a decrease in tracer activity both within the primary intraprostatic lesion and suspicious lymph nodes. The primary lesion mean SUV prior to treatment was 4.46±1.14 and 2.37±1.07 following initiation of ADT (p=0.0007). The primary lesion maximum SUV prior to treatment was 7.13±1.70 and 3.54±2.04 following initiation of ADT (p=0.0006). Conclusions: Fluciclovine-PET tracer activity in patients with PCa undergoing ADT appears to correlate with decrease in serum PSA. Fluciclovine-PET imaging may be useful in monitoring response to ADT, particularly if there is a failure of appropriate PSA response. Clinical trial information: NCT03264456.
Enzalutamide (E) re-challenge as second-line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with first-line enzalutamide + docetaxel (D): Preliminary results of a post-progression analysis of CHEIRON trial.
Authors: Orazio Caffo, Michele Aieta, Erica Palesandro, Marianna Macerelli, Claudia Mucciarini, Maurizio Nicodemo, Ugo De Giorgi, Donata Sartori, Lucia Fratino, Roberto Iacovelli, Sabrina Rossetti, Daniela Scapoli, Franco Morelli, Francesco Carrozza, Franco Nole, Vittorina Zagonel, Carlo Messina, Donatello Gasparro
Journal: Journal of Clinical Oncology (2020)

123 Background: CHEIRON trial was a phase II study which randomized previously untreated mCRPC pts to receive D 75 mg/m2 IV d1 q3w for 8 courses alone or plus E 160 mg PO daily. As per protocol, E was administered in experimental arm for only 24 wks until D conclusion. The study met its primary endpoint since the rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). The clinicians were asked to consider an E re-challenge as first post-progression treatment for those pts without disease progression at the chemotherapy end in the experimental arm. We presented the preliminary analysis of E activity in post-progression setting of CHEIRON DE arm. Methods: We evaluated all patients enrolled in the experimental arm, focusing on pts who received E as first post-progression treatment. We collected data concerning the treatment duration and disease control and compared the outcomes of pts treated with E re-challenge with those of pts who received other treatments at the time of first progression after experimental therapy. Results: Among the 120 pts who received DE experimental arm, 101 did not show a disease progression and 82 received a second-line active treatment: 54 (66%) were treated with E, the other received abiraterone (10 pts), cabazitaxel (13 pts), and radium 223 (5 pts). The median interval between the end of DE and the start of E re-challenge was 7.6 mos (range 0.9-18.4 mos). At a median follow-up of 15.5 mos, the median duration of E re-challenge was 9.8 mos (range 1.9-30.9) with 22 pts still on treatment. Pts who received E rechallenge showed a median progression free survival of 11.4 mos which was significantly longer compared to 4.5 mos showed in pts who received other treatments (p &lt; 0.0001). The median overall survival was 20.4 mos and 12.3 mos, respectively (p = NS). Conclusions: In pts who received first-line DE in the CHEIRON trial, the reintroduction of E after a per-protocol discontinuation demonstrated to be feasible, with a prolonged disease control compared to the other post-progression therapeutic options. Clinical trial information: NCT02453009.
Impact of 18FDG-PET CT in the management of invasive bladder cancer.
Authors: Pauline Bertolaso, Véronique Brouste, Anne Laure Cazeau, Henri De Clermont-Gallerande, Franck Bladou, Mathilde Cabart, Alain Ravaud, Marine Gross-Goupil
Journal: Journal of Clinical Oncology (2020)

444 Background: Guidelines do not recommend FDG-Positron Emission Tomography (PET) Computed Tomography (CT) for the staging of Muscle Invasive Bladder Cancer (MIBC), but rather CT scan for lymph node (LN) and metastatic staging, despite its low accuracy. We performed a retrospective analysis of patients (pts) with MIBC who had a FDG-PET CT for staging, indicated by multidisciplinary team, in two centers, and analyzed its utility in this setting. Methods: All pts who had a FDG-PET CT performed at the time of diagnosis of MIBC from 01/2005 to 12/2017 in Bordeaux (Bergonie Institute and University Hospital) were retrospectively reviewed. Nodal and metastatic staging on CT and FDG-PET CT were done independently according to the 8 th TNM classification. The aims of the study were to evaluate the accuracy of the FDG-PET CT for LN staging and to determine the rate of treatment modification (neoadjuvant chemotherapy for curative intent, no surgery for metastatic disease), according to FDG-PET CT results. Results: Among the 130 pts included, with a median age of 65 years, 74% were considered free from nodal metastasis (N0) by CT whereas only 44% were N0 from FDG-PET CT. Based on CT results, 88% of pts were free from distant metastasis (M0) but only 75% were classified M0, on FDG-PET CT. Accuracy of LN staging for CT and FDG-PET CT at initial diagnosis were analyzed for 85 pts (including 70 pts treated with neoadjuvant chemotherapy) and compared to pathological examination of resected LN. Sensitivity of FDG-PET CT was better than CT (respectively 80.8% versus 26.9%) but the specificity was low (respectively 54.2% versus 83.1%). Youden index was better for FDG-PET CT (0.35; 0.1 for CT), being more accurate for determining LN staging of MIBC. FDG-PET CT findings allowed a treatment decision modification in 34/130 pts (26.1%): therapeutic intensification in 12 pts (9.2%), including surgery not previously indicated, modified radiotherapy; or de-escalation in 22 pts (16.9%), mostly avoiding surgery. Conclusions: FDG-PET CT is more sensitive to detect LN involvement at initial diagnosis of MIBC than standard CT scan. Moreover, in the present study, treatment decisions were modified, according to FDG-PET CT results, in a quarter of pts according to LN and distant metastatic staging.
Big-game hunting in the history of epidemics
Authors: Christoph Gradmann
Journal: The Lancet Infectious Diseases (2020)

Frank Snowden, historian at Yale University, is an established expert of the history of epidemics, in particular through his work on cholera and malaria in Italy. He has now taken his career-long passion for epidemics into a new book, Epidemics and Society: From Black Death to the Present. Covering roughly a millennium on about 550 pages is no small task. Snowden does it by focusing on landmark epidemic infectious diseases, such as the plague, cholera, and HIV/AIDS, rather than giving a comprehensive overview of historical epidemiology.
Contrasting microbiotas between Finnish and Estonian infants: Exposure to <i>Acinetobacter</i> may contribute to the allergy gap
Authors: Lasse Ruokolainen, Anna Parkkola, Antti Karkman, Hanna Sinkko, Aleksandr Peet, Anu‐Maaria Hämäläinen, Leena von Hertzen, Vallo Tillmann, Katriina Koski, Suvi M. Virtanen, Onni Niemelä, Tari Haahtela, Mikael Knip
Journal: Allergy (2020)

Abstract Background Allergic diseases are more common in Finland than in Estonia, which—according to the biodiversity hypothesis—could relate to differences in early microbial exposures. Methods We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6‐month‐old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. Results Sensitization was differentially targeted between populations, as egg‐specific and birch pollen‐specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genus Acinetobacter was more abundant in Estonian skin and nasal samples. Particularly, the strain‐level profile of Acinetobacter lwoffii was more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE‐related sensitization, but only in Finland. While land‐use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genus Acinetobacter . Breastfeeding affected gut microbial composition and seemed to protect from sensitization. Conclusions In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genus Acinetobacter in the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.
Intra-articular sprifermin reduces cartilage loss in addition to increasing cartilage gain independent of location in the femorotibial joint: post-hoc analysis of a randomised, placebo-controlled phase II clinical trial
Authors: Felix Eckstein, Jeffrey L Kraines, Aida Aydemir, Wolfgang Wirth, Susanne Maschek, Marc C Hochberg
Journal: Annals of the Rheumatic Diseases (2020)

In the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.Patients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.Thinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.Sprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.NCT01919164.
Alveolar macrophage P2Y6 receptors counterbalance leukotriene-dependent type 2 lung immunopathology priming function
Authors: Jun Nagai, Junrui Lin, Barbara Balestrieri, Laura Fanning, Timothy Kyin, Haley Cirka, Edy Kim, Patrick Brennan, Joshua Boyce
Journal: Journal of Allergy and Clinical Immunology (2020)
Bilateral median nerve neuritis after chikungunya virus infection
Authors: Fernanda Cristina Rueda-Lopes, Cristiane N Soares, Iracema Forni Vieira, Silvana Mendonça, Ezequias Batista Martins, Suzannah Lant, Patrícia C Sequeira, Tom Solomon, Ana Maria Bispo de Filippis, Guilherme Calvet, Patrícia Brasil
Journal: The Lancet Infectious Diseases (2020)
A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer
Authors: M.P. Kolinsky, P. Rescigno, D. Bianchini, Z. Zafeiriou, N. Mehra, J. Mateo, V. Michalarea, R. Riisnaes, M. Crespo, I. Figueiredo, S. Miranda, D. Nava Rodrigues, P. Flohr, N. Tunariu, U. Banerji, R. Ruddle, A. Sharp, J. Welti, M. Lambros, S. Carreira, F.I. Raynaud, K.E. Swales, S. Plymate, J. Luo, H. Tovey, N. Porta, R. Slade, L. Leonard, E. Hall, J.S. de Bono
Journal: Annals of Oncology (2020)

Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss.
Managing multimorbidity needs time and thought
Authors: Imogen Sutherland, Samad Samadian
Journal: BMJ (2020)

Medical admissions are caused by a domino effect of environmental, social, mental, and physical factors, yet we only treat that last domino. Throughout our medical training, we have been reminded that time is of the essence—see more patients, in less time, diagnose and start treatment in the least number of minutes before moving on to “pick up a new …