tbuckley/cabot-search huggingface dataset:
Quantitative phosphoproteomics uncovers synergy between DNA-PK and FLT3 inhibitors in acute myeloid leukaemia
Authors: Heather C. Murray, Anoop K. Enjeti, Richard G. S. Kahl, Hayley M. Flanagan, Jonathan Sillar, David A. Skerrett-Byrne, Juhura G. Al Mazi, Gough G. Au, Charles E. de Bock, Kathryn Evans, Nathan D. Smith, Amanda Anderson, Brett Nixon, Richard B. Lock, Martin R. Larsen, Nicole M. Verrills, Matthew D. Dun
Journal: Leukemia (2020)

Acute myeloid leukaemia (AML) is the most common and aggressive form of acute leukaemia in adults.The most common driver mutations in AML are activating mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, occurring in approximately one third of cases [1].Internal tandem duplication (FLT3-ITD) mutations in the FLT3 juxtamembrane domain are the most common (~25%), and are associated with genomic instability, and intermediateadverse prognosis [2].Point mutations in the FLT3 activation loop, most commonly at amino acid D835, occur in ~8% of AML patients and their prognostic effect remains to be defined.The landscape of treatment options for AML is rapidly changing, however there remains limited durable treatment options for molecular subtypes such as mutant-FLT3 AML.To identify novel therapeutic targets, we undertook quantitative phosphoproteomic profiling of primary AML blasts (Supplementary Methods) [3].Across seven patient samples (3 × wildtype-FLT3, 4 × mutant-FLT3; Tables S1 andS2), 4345 unique phosphosites were identified from 1994 proteins, with expected ratios of serine, threonine, and tyrosine sites [pS:pT:pY 88.9%:10.6%:0.6%].The top pathways phosphorylated in AML blasts were growth and survival signalling pathways (ERK/MAPK, AMPK signalling, Fig. S1) and DNA damage repair signalling pathways (ATM signalling, DNA double strand break (DSB) repair, Fig. S1).Kinase substrate enrichment analysis (KSEA) revealed activation of the cell cycle and apoptosis regulator, Casein Kinase 2 (CK2-A1), in all blast samples (Figs.1a andS2).Increased CK2-A1 expression has been demonstrated in a range of haematological cancers, including AML; driving cell proliferation, survival, and drug resistance [4].
Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy
Authors: Gabriela Marsavela, Jenny Lee, Leslie Calapre, Stephen Q. Wong, Michelle R. Pereira, Ashleigh C. McEvoy, Anna L. Reid, Cleo Robinson, Lydia Warburton, Afaf Abed, Muhammad A. Khattak, Tarek M. Meniawy, Sarah-Jane Dawson, Shahneen Sandhu, Matteo S. Carlino, Alexander M. Menzies, Richard A. Scolyer, Georgina V. Long, Benhur Amanuel, Michael Millward, Melanie R. Ziman, Helen Rizos, Elin S. Gray
Journal: Clinical Cancer Research (2020)

We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings.In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07-0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22-0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti-PD-1 monotherapy, relative to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors.Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.
A Further Weakening of Contraceptive Coverage Under the Affordable Care Act
Authors: Erica S. Turret, Katherine L. Kraschel, Gregory Curfman
Journal: JAMA Internal Medicine (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure
Authors: Michinari Nakamura, Natalija Odanovic, Yasuki Nakada, Satomi Dohi, Peiyong Zhai, Andreas Ivessa, Zhi Yang, Maha Abdellatif, Junichi Sadoshima
Journal: Cardiovascular Research (2020)

Abstract Aims A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how an LC diet impacts on cardiac pathology during haemodynamic stress remains elusive. This study evaluated the effects of an LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodelling. Methods and results Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, haemodynamic, histological, and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signalling. Conclusion Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.
FRI0118 A clinicopathological study of tubulointerstitial changes in patients with lupus nephritis
Authors: S Mulic, H Seleskovic, E Cickusic, S Trnacevic, E Zerem, Z Karasalihovic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The prognostic importance of renal involvement in Systemic Lupus Erythematosus (SLE) is well known. Predominant interstitial nephritis is a rare manifestation of SLE. The prognostic importance of histopathological tubulointerstitial (TIC) changes in renal tissue in patients with lupus nephritis (LN) is very little known. <h3>Objectives</h3> Our objectives were to more precisely determine TIC in the renal tissue and correlate these data with clinical features, daily proteinuria and 24-hour creatinine clearance in pts with LN. Our long-term goal is to identify pts during clinical quiescence who may be at high risk of developing progression to renal failure from LN. <h3>Methods</h3> Renal biopsies from 26 pts were analysed with emphasis on TIC. At the time of biopsy all pts had defined clinical evidence of active LN. Presence and intensity of oedema, inflammatory mononuclear infiltrate, fibrosis, hyaline casts and tubular atrophy were determined. TIC were graded from 0 to 3 (absent, mild, moderate and severe). We correlated these results with clinical data of 24-hour creatinine clearance (CC) and 24-hour urine total protein excretion (TP) at pre-treatment and post-treatment period. <h3>Results</h3> Patients were divided into 4 group: first group with absent TIC (0 score) 6 pts with TP mean 2.17 gr/24 h, CC mean 1.32 ml/s; second group with mild TIC (1–5 score), 12 pts with TP mean 2.61 gr/24 h, CC mean 0.76 ml/s; third group with moderate TIC (6 do 10 score) 5 pts with TP mean 2.67 gr/24 h, CC 0.95 ml/s; forth group with severe TIC (11 to 15 score) 3 pts with TP mean 1.52, CC mean 0.37 ml/s. These analyses we repeated after treatment with corticosteroids and citotoxyc drugs at period of 3 to 6 months and correlated with previous data. Significant results occurred for TP in first group (p &lt; 0.05) and in second group (p &lt; 0.01), as well as in second group for CC (p &lt; 0.05). Significant improvement for both parameters occurred in group of 12 pts with mild TIC. (TP p &lt; 0.01; CC p &lt; 0.05). In group of pts with severe TIC, TP has decreased as well as CC. <h3>Conclusion</h3> TP decrease as well as increase of CC correlated well with mild degree of TIC. TIC could be prognostic predictors in LN. This has to be proved with a greater number of pts.
Butyrate mediates anti-inflammatory effects of<i>Faecalibacterium prausnitzii</i>in intestinal epithelial cells through<i>Dact3</i>
Authors: Marion Lenoir, Rebeca Martín, Edgar Torres-Maravilla, Sead Chadi, Pamela González-Dávila, Harry Sokol, Philippe Langella, Florian Chain, Luis G. Bermúdez-Humarán
Journal: Gut Microbes (2020)

The commensal bacterium Faecalibacterium prausnitzii plays a key role in inflammatory bowel disease (IBD) pathogenesis and serves as a general health biomarker in humans. However, the host molecular mechanisms that underlie its anti-inflammatory effects remain unknown. In this study we performed a transcriptomic approach on human intestinal epithelial cells (HT-29) stimulated with TNF-α and exposed to F. prausnitzii culture supernatant (SN) in order to determine the impact of this commensal bacterium on intestinal epithelial cells. Moreover, modulation of the most upregulated gene after F. prausnitzii SN contact was validated both in vitro and in vivo. Our results showed that F. prausnitzii SN upregulates the expression of Dact3, a gene linked to the Wnt/JNK pathway. Interestingly, when we silenced Dact3 expression, the effect of F. prausnitzii SN was lost. Butyrate was identified as the F. prausnitzii effector responsible for Dact3 modulation. Dact3 upregulation was also validated in vivo in both healthy and inflamed mice treated with either F. prausnitzii SN or the live bacteria, respectively. Finally, we demonstrated by colon transcriptomics that gut microbiota directly influences Dact3 expression. This study provides new clues about the host molecular mechanisms involved in the anti-inflammatory effects of the beneficial commensal bacterium F. prausnitzii.
Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity
Authors: Tyler J. Ripperger, Jennifer L. Uhrlaub, Makiko Watanabe, Rachel Wong, Yvonne Castaneda, Hannah A. Pizzato, Mallory R. Thompson, Christine Bradshaw, Craig C. Weinkauf, Christian Bime, Heidi L. Erickson, Kenneth Knox, Billie Bixby, Sairam Parthasarathy, Sachin Chaudhary, Bhupinder Natt, Elaine Cristan, Tammer El Aini, Franz Rischard, Janet Campion, Madhav Chopra, Michael Insel, Afshin Sam, James L. Knepler, Andrew P. Capaldi, Catherine M. Spier, Michael D. Dake, Taylor Edwards, Matthew E. Kaplan, Serena Jain Scott, Cameron Hypes, Jarrod Mosier, David T. Harris, Bonnie J. LaFleur, Ryan Sprissler, Janko Nikolich-Žugich, Deepta Bhattacharya
Journal: Immunity (2020)
Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group
Authors: Gene Y. Im, Jessica L. Mellinger, Adam Winters, Elizabeth S. Aby, Zurabi Lominadze, John Rice, Michael R. Lucey, Juan P. Arab, Aparna Goel, Loretta L. Jophlin, Courtney B. Sherman, Richard Parker, Po-Hung Chen, Deepika Devuni, Sandeep Sidhu, Winston Dunn, Gyongyi Szabo, Ashwani K. Singal, Vijay H. Shah
Journal: Clinical Gastroenterology and Hepatology (2020)
HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors
Authors: Yu-Ru Lin, K. Rachael Parks, Connor Weidle, Anika S. Naidu, Arineh Khechaduri, Andrew O. Riker, Brittany Takushi, Jung-Ho Chun, Andrew J. Borst, David Veesler, Andrew Stuart, Parul Agrawal, Matthew Gray, Marie Pancera, Po-Ssu Huang, Leonidas Stamatatos
Journal: Immunity (2020)
Exhibition: The Theatre of Life and Death
Authors: Jules Marshall
Journal: BMJ (2003)

Having freed itself from the Spanish empire, the Republic of the Seven United Provinces of the Netherlands was by the 17th century a superpower to rival Britain. Known primarily through its art, the Dutch Golden Age was also a period of great scientific and medical advance.​advance.




Figure 1



A full scale copy of Leiden University's anatomy theatre




The new ideas of the Italian renaissance filtered north, driving out the medieval superstitions, including those related to health and illness. Works such as Vesalius's Atlas, new herbalist volumes, and discoveries both earthly and celestial inspired the protestant Dutch to build their own new age of research and anatomy.

It was the beginning of the end of seeing illness as God's will and the start of seeing it as something fathomable, preventable, and treatable. Humanism and the reformation had created the idea that man was on the earth to be productive; even the poorest had to work, so they had to be kept well enough to do so. “The Theatre of Life and Death” is an attempt to show how the powerful Dutch cities dealt with sickness and death as they took over the Catholic church's obligations to provide for the poor and elderly.

In 1636 the building that now houses the Boerhaave Museum, where the exhibition is on display, became the first teaching hospital this side of the Alps. Twelve beds were set aside for “interesting cases” to be poked, prodded, and discussed in Latin by medical students. Later, Herman Boerhaave developed teaching methods here that drew students from around the world, were widely copied from Philadelphia to Moscow, and remain influential today.

The exhibition is centred on a full scale copy of Leiden University's anatomy theatre, a recreated surgeon's shop, and a hospital ward of the day. Within this framework is a wide range of medicine related art and technology, from wax cadavers by Petrus Koning, natural history collections, and examples of how other fields such as astronomy and cartography were contributing to raising the level of medical knowledge.

There are icons and statues as well as oil paintings of the time, exhorting the public to honour the new medical professions, as well as the regentessen or governors of the new hospitals who made the financial and appointment decisions.

The Four Guises of the Physician (Anon, 1625 1600) may ring some emotional bells with modern medics: the physician on house call is portrayed first as a messiah-like saviour, then with decreasing appreciation as the patient recovers, until by picture four (the presentation of the bill) he is depicted as the devil incarnate.
Time efficiency analysis for undersampled quantitative MRI acquisitions
Authors: Riwaj Byanju, Stefan Klein, Alexandra Cristobal-Huerta, Juan A. Hernandez-Tamames, Dirk H.J. Poot
Journal: Medical Image Analysis (2022)

To realize Quantitative MRI (QMRI) with clinically acceptable scan time, acceleration factors achieved by conventional parallel imaging techniques are often inadequate. Further acceleration is possible using model-based reconstruction. We propose a theoretical metric called TEUSQA: Time Efficiency for UnderSampled QMRI Acquisitions to inform sequence design and sample pattern optimisation. TEUSQA is designed for a particular class of reconstruction techniques that directly estimate tissue parameters, possibly using prior information to regularize the estimation. TEUSQA can be used to evaluate undersampling patterns for multi-contrast QMRI sequences targeting any tissue parameter. To verify the time efficiency predicted by TEUSQA, we performed Monte Carlo simulations and an accelerated parameter mapping with two sequences (Inversion prepared fast spin echo for T1 and T2 mapping and 3D GRASE for T2 and B0 inhomogeneity mapping). Using TEUSQA, we assessed several ways to generate undersampling patterns in silico, providing insight into the relation between sample distribution and time efficiency for different acceleration factors. The time efficiency predicted by TEUSQA was within 15% of that observed in the Monte Carlo simulations and the prospective acquisition experiment. The assessment of undersampling patterns showed that a class of good patterns could be obtained by low-discrepancy sampling. We believe that TEUSQA offers a valuable instrument for developers of novel QMRI sequences pushing the boundaries of acceleration to achieve clinically feasible protocols. Finally, we applied a time-efficient undersampling pattern selected using TEUSQA for a 32-fold accelerated scan to map T1 & T2 mapping of a healthy volunteer.
THU0034 Higher il-10 concentrations in the synovial fluid from ra patients when compared with spondyloarthropathy-derived fluids
Authors: B Moeller, U Kessler, N Kukoc-Zivojnov, J Kaltwasser
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Several investigations of synovial fluid (SF) and membrane derived T cells show a predominant Th1 response with high IFN-gamma production from rheumatoid arthritis (RA), and a predominant Th2 response with high IL-4 and IL-10 production in T cells from spondyloarthropathy (SpA) joints. <h3>Objectives</h3> To investigate the concentrations of IFN-gamma, TNF-alpha, IL-4, IL-10, the Th1 propagating cytokines IL-12 and IL-18, and the monokine IL-1 in sera and synovial fluids from RA and SpA patients. <h3>Methods</h3> Patients were selected according to the ACR classification criteria for RA (n = 13), and the ESSG classification criteria for SpA (n = 14). Cytokine concentrations were measured using commercial ELISA kits. Results are expressed as mean ± standard deviation, significance was calculated using the Mann-Whitney U-test for untailed groups. Sera from 8 healthy donors served as controls. <h3>Results</h3> IFN-gamma concentrations were significantly lower (4,3 ± 2,6 pg/ml), but IL-18 (78,8 ± 29,3 pg/ml), TNF-alpha (105,4 ± 40,9 pg/ml), and IL-10 (100,1 ± 69,7 pg/ml) concentrations were significantly higher in RA than in SpA-SF (IFN-gamma 12,9 ± 10,4 pg/ml, p = 0,009, IL-18 55,1 ± 44,1 pg/ml, p = 0,038, TNF-alpha 74,1 ± 85,0 pg/ml, p = 0,044, IL-10 14,1 ± 19,9, p &lt; 0,0001). IL-4 and IL-12 concentrations were rather low in RA- and SpA-SF. Serum concentrations of all investigated cytokines in RA and SpA differed – if at all -only marginally from the situation in healthy donors. <h3>Conclusion</h3> Synovial fluid concentrations of the Th1 and Th2 cytokines in RA and SpA do not generally reflect the state of Th1/Th2 balance at the single cell level. There is strong evidence for substantially higher amounts of IL-10 in RA than SpA synovium, reflecting strong antiiflammatory processes are present in RA synovium. The observed Th1/Th2 balances in both investigated diseases are not explained by the corresponding IL-12 and IL-18 SF concentrations.
Predicting in vivo therapeutic efficacy of bioorthogonally labeled endothelial progenitor cells in hind limb ischemia models via non-invasive fluorescence molecular tomography
Authors: Seungho Lim, Hong Yeol Yoon, Soon-Jung Park, Sukyung Song, Man Kyu Shim, Suah Yang, Sun-Woong Kang, Dong-Kwon Lim, Byung-Soo Kim, Sung-Hwan Moon, Kwangmeyung Kim
Journal: Biomaterials (2020)
Discovery of a potent and dual-selective bisubstrate inhibitor for protein arginine methyltransferase 4/5
Authors: Ayad A. Al-Hamashi, Dongxing Chen, Youchao Deng, Guangping Dong, Rong Huang
Journal: Acta Pharmaceutica Sinica B (2020)

Protein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine (SAM) analogue moiety and a tripeptide through an alkyl substituted guanidino group. Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration (IC50) of 2.8 and 0.42 nmol/L, respectively. Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases. This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs, providing valuable probes for future structural studies.
Scientific Ambiguity in the Time of Coronavirus Disease 2019—Reply
Authors: Alfredo Tagarro, Cinta Moraleda, Cristina Calvo
Journal: JAMA Pediatrics (2020)

Alfredo Tagarro, PhD, MD; Cristina Epalza, PhD, MD; Mar Santos, PhD, MD; Francisco José Sanz-Santaeufemia, PhD, MD; Enrique Otheo, PhD, MD; Cinta Moraleda, PhD, MD; Cristina Calvo, PhD, MD