tbuckley/cabot-search huggingface dataset:
The use of infrared spectroscopy to provide an estimation of the gross biochemistry associated with colorectal pathologies
Authors: J. J. Wood, C. Kendall, N. Stone, N. Shepherd, T. Cook
Journal: Gut (2011)

<h3>Introduction</h3> The gold standard assessment of tissue biopsies from colonoscopy is histopathology. Infrared spectroscopy has potential to map biochemical changes across a tissue section distinguishing between different disease states.1 This may aid the pathologist or could lead to automated histopathological processing. This study attempted to determine biochemical changes in colorectal disease using infrared spectroscopy. <h3>Methods</h3> Tissue biopsies were snap frozen at colonoscopy. 2-D spectral datasets were obtained from 10 micron thick sections of specimens, thawed to room temperature, using a Perkin Elmer infrared imaging system in transmission mode. Contiguous tissue sections stained with H&amp;E were reviewed by a senior consultant pathologist for comparison. Reference spectra from pure biochemicals (Sigma-Aldridge) were measured. Dot products2 of these reference spectra with the mapped spectral datasets were calculated to provide a correlation estimate represented as a pseudocolour image. Ordinary least squares analysis3 was also used to estimate the relative proportions of biochemical constituents from regions of interest. <h3>Results</h3> Biochemical dot product correlation maps were obtained from normal and inflammatory tissue, hyperplastic polyps, adenomatous polyps and cancer. An example is shown in the accompanying figure. Distributions and proportions of DNA, glycogen, lipids and proteins were compared between areas of pathological interest (see figure 1). <h3>Conclusion</h3> Infrared spectroscopy provides valuable biochemical information within colorectal pathologies. This information may aid the diagnosing pathologist and help develop automated histopathological processing.
The cellular architecture of the antimicrobial response network in human leprosy granulomas
Authors: Feiyang Ma, Travis K. Hughes, Rosane M. B. Teles, Priscila R. Andrade, Bruno J. de Andrade Silva, Olesya Plazyo, Lam C. Tsoi, Tran Do, Marc H. Wadsworth, Aislyn Oulee, Maria Teresa Ochoa, Euzenir N. Sarno, M. Luisa Iruela-Arispe, Eynav Klechevsky, Bryan Bryson, Alex K. Shalek, Barry R. Bloom, Johann E. Gudjonsson, Matteo Pellegrini, Robert L. Modlin
Journal: Nature Immunology (2021)
Investigating raised creatine kinase
Authors: Eun Ji Kim, Anthony S Wierzbicki
Journal: BMJ (2021)

A 76 year old man with hypercholesterolaemia is referred to the lipid clinic because of persistently raised creatine kinase activity of 1000 IU/L or above (reference range 40-320 IU/L) after trying multiple statins. He describes no significant myalgia but had some proximal muscle weakness, which is demonstrated when he stands up from a seated position and when walking upstairs. 

Creatine kinase (known previously as creatine phosphokinase or CPK) is distinct from creatinine and is a biomarker of muscle damage. The reference range for normal creatine kinase is 40‐320 IU/L for men and 25‐200 IU/L for women, though this may vary across laboratories and assays. Creatine kinase levels are dependent on age, sex, and muscle mass: the upper limit of normal (ULN) for men is higher than in women, and ageing is associated with reduced muscle mass, so minor increases in creatine kinase may indicate a greater extent of muscle damage in older adults.1 Pathologies involving muscle include myalgia (muscle pain with no creatine kinase rise), myopathy (muscle pain with creatine kinase rise), and rhabdomyolysis (muscle pain, weakness, and/or swelling with myoglobinuria and elevated creatine kinase). Creatine kinase can also be elevated without any muscle symptoms.2 Moreover, no clear correlation exists between creatine kinase activity and the extent of actual muscle injury. That said, creatine kinase >5000 IU/L (10-50 times the upper limit of normal) should prompt consideration of rhabdomyolysis.

Most cases of raised creatine kinase can …
Reply to: “Progressive cholangiopathy in COVID-19 patients: Other possible diagnoses than ketamine-induced cholangiopathy should be considered”
Authors: Vincent Mallet, Vincent Mallet, Kilian Bock, Mourad Dellagi, Marion Tano, Virginie Siorat, Nathanaël Beeker, Pascal Paubel, Paul Doumbe Mandengue, Nicolas Dufour, Torsten Voigtländer, Jean-Damien Ricard, Pierre Isnard, Vincent Frochot, Emmanuel Letavernier, Lucile Moga, Amandine Landrieux, Pierre-Emmanuel Rautou, Nathalie Pons-Kerjean, Anaïs Vallet-Pichard, Clémence Hollande, Hélène Fontaine, Laurent Chouchana, Coralie Gernez, Carole Burger, Anne Scemla, Christian de Tymowski, François Depret, Emmanuel Dudoignon, Lionel Lamhaut, Rémi Flicoteau, Géraldine Rousseau, Jean-Paul Duong Van Huyen, Jean-Michel Correas, Heiner Wedemeyer, Stanislas Pol
Journal: Journal of Hepatology (2021)
Advancing Therapy in Suboptimally Controlled Basal Insulin–Treated Type 2 Diabetes: Clinical Outcomes With iGlarLixi Versus Premix BIAsp 30 in the SoliMix Randomized Controlled Trial
Authors: Julio Rosenstock, Rifat Emral, Leobardo Sauque-Reyna, Viswanathan Mohan, Carlos Trescolí, Saud Al Sifri, Nebojsa Lalic, Agustina Alvarez, Pascaline Picard, Mireille Bonnemaire, Nacima Demil, Rory J. McCrimmon
Journal: Diabetes Care (2021)

OBJECTIVE To directly compare the efficacy and safety of a fixed-ratio combination, of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi), with those of a premix insulin analog, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine) (BIAsp 30) as treatment advancement in type 2 diabetes suboptimally controlled on basal insulin plus oral antihyperglycemic drugs (OADs). RESEARCH DESIGN AND METHODS In SoliMix, a 26-week, open-label, multicenter study, adults with suboptimally controlled basal insulin–treated type 2 diabetes (HbA1c ≥7.5% and ≤10%) were randomized to once-daily iGlarLixi or twice-daily BIAsp 30. Primary efficacy end points were noninferiority in HbA1c reduction (margin 0.3%) or superiority in body weight change for iGlarLixi versus BIAsp 30. RESULTS Both primary efficacy end points were met: after 26 weeks, baseline HbA1c (8.6%) was reduced by 1.3% with iGlarLixi and 1.1% with BIAsp 30, meeting noninferiority (least squares [LS] mean difference −0.2% [97.5% CI −0.4, −0.1]; P &amp;lt; 0.001). iGlarLixi was also superior to BIAsp 30 for body weight change (LS mean difference −1.9 kg [95% CI −2.3, −1.4]) and percentage of participants achieving HbA1c &amp;lt;7% without weight gain and HbA1c &amp;lt;7% without weight gain and without hypoglycemia (all P &amp;lt; 0.001). iGlarLixi was also superior versus BIAsp 30 for HbA1c reduction (P &amp;lt; 0.001). Incidence and rates of American Diabetes Association level 1 and 2 hypoglycemia were lower with iGlarLixi versus BIAsp 30. CONCLUSIONS Once-daily iGlarLixi provided better glycemic control with weight benefit and less hypoglycemia than twice-daily premix BIAsp 30. iGlarLixi is a more efficacious, simpler, and well-tolerated alternative to premix BIAsp 30 in suboptimally controlled type 2 diabetes requiring treatment beyond basal insulin plus OAD therapy. Video 1
Clonal hematopoiesis and its emerging effects on cellular therapies
Authors: Malte von Bonin, Helena Klara Jambor, Raphael Teipel, Friedrich Stölzel, Christian Thiede, Frederik Damm, Frank Kroschinsky, Johannes Schetelig, Triantafyllos Chavakis, Martin Bornhäuser
Journal: Leukemia (2021)

Abstract The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.
Abstract 67: Metabolic Programming Regulates Proliferation and Binucleation of Postnatal Cardiomyocytes
Authors: Daniela Liccardo, Ryan LaCanna, Ying Tian
Journal: Circulation Research (2016)

In contrast to adult, neonatal cardiomyocytes are able to proliferate and lose this capacity soon after birth when they withdraw from the cell cycle, become binucleated and differentiate. The arrest of cardiomyocytes cell cycle can be reversible for a short period, conferring the neonatal heart a regenerative potential within the first week of postnatal life. In the timeframe surrounding birth, heart maturation is also characterized by a change in energy metabolism, switching from glycolysis to beta-oxidation. However little is known about how metabolic programming in postnatal cardiomyocytes regulates their ability to proliferate, become binucleated and differentiate. In this study, we show that blocking beta-oxidation in mouse neonatal cardiomyocytes with etomoxir treatment promotes glycolysis and cell cycle re-entry, while increasing fatty acid beta-oxidation but reducing glycolysis leads to a decrease of the number of proliferating cardiomyocytes. In neonatal mice our data demonstrate that cardiomyocytes undergo binucleation and differentiation during the first week after birth and this process is correlated with the upregulation of the natriuretic peptides, ANP and BNP expression. Notably, in the postnatal mouse heart, beta-oxidation blockade through in vivo etomoxir injections, increases ventricular cardiomyocytes number, decreases natriuretic peptides expression and reduces the conversion of cardiomyocytes from a mononucleated to a binucleated phenotype. These findings highlight the importance of metabolic programming in regulating cardiomyocyte proliferation and suggest a potential therapeutic target for heart regeneration by modulating energy metabolic programming.
Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative
Authors: Philippe Aftimos, Mafalda Oliveira, Alexandre Irrthum, Debora Fumagalli, Christos Sotiriou, Einav Nili Gal-Yam, Mark E. Robson, Justin Ndozeng, Angelo Di Leo, Eva M. Ciruelos, Evandro de Azambuja, Giuseppe Viale, Elsemieke D. Scheepers, Giuseppe Curigliano, Judith M. Bliss, Jorge S. Reis-Filho, Marco Colleoni, Marija Balic, Fatima Cardoso, Joan Albanell, Caroline Duhem, Sandrine Marreaud, Dario Romagnoli, Beatriz Rojas, Andrea Gombos, Hans Wildiers, Angel Guerrero-Zotano, Peter Hall, Andrea Bonetti, Karolina Fs Larsson, Martina Degiorgis, Silvia Khodaverdi, Richard Greil, Ásgerdur Sverrisdóttir, Marta Paoli, Ethel Seyll, Sibylle Loibl, Barbro Linderholm, Gabriele Zoppoli, Nancy E. Davidson, Oskar Th Johannsson, Philippe L. Bedard, Sherene Loi, Susan Knox, David A. Cameron, Nadia Harbeck, Maite Lasa Montoya, Mariana Brandão, Andrea Vingiani, Carmela Caballero, Florentine S. Hilbers, Lucy R. Yates, Matteo Benelli, David Venet, Martine J. Piccart
Journal: Cancer Discovery (2021)

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.
The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance
Authors: Sunil K. Joshi, Tamilla Nechiporuk, Daniel Bottomly, Paul D. Piehowski, Julie A. Reisz, Janét Pittsenbarger, Andy Kaempf, Sara J.C. Gosline, Yi-Ting Wang, Joshua R. Hansen, Marina A. Gritsenko, Chelsea Hutchinson, Karl K. Weitz, Jamie Moon, Francesca Cendali, Thomas L. Fillmore, Chia-Feng Tsai, Athena A. Schepmoes, Tujin Shi, Osama A. Arshad, Jason E. McDermott, Ozgun Babur, Kevin Watanabe-Smith, Emek Demir, Angelo D'Alessandro, Tao Liu, Cristina E. Tognon, Jeffrey W. Tyner, Shannon K. McWeeney, Karin D. Rodland, Brian J. Druker, Elie Traer
Journal: Cancer Cell (2021)

Our study details the stepwise evolution of gilteritinib resistance in FLT3-mutated acute myeloid leukemia (AML). Early resistance is mediated by the bone marrow microenvironment, which protects residual leukemia cells. Over time, leukemia cells evolve intrinsic mechanisms of resistance, or late resistance. We mechanistically define both early and late resistance by integrating whole-exome sequencing, CRISPR-Cas9, metabolomics, proteomics, and pharmacologic approaches. Early resistant cells undergo metabolic reprogramming, grow more slowly, and are dependent upon Aurora kinase B (AURKB). Late resistant cells are characterized by expansion of pre-existing NRAS mutant subclones and continued metabolic reprogramming. Our model closely mirrors the timing and mutations of AML patients treated with gilteritinib. Pharmacological inhibition of AURKB resensitizes both early resistant cell cultures and primary leukemia cells from gilteritinib-treated AML patients. These findings support a combinatorial strategy to target early resistant AML cells with AURKB inhibitors and gilteritinib before the expansion of pre-existing resistance mutations occurs.
Abstract 122: Pkialpha Protects Hearts From Beta-adrenergic Overstimulation
Authors: Xiaoying Zhang, Ying Li, Xiaojie Ai, Mingxin Tang, Christopher Szeto, Xiang Hua, Xiongwen Chen
Journal: Circulation Research (2016)

Introduction: Protein kinase inhibitor peptide α (PKIα) isoforms are abundantly expressed endogenous inhibitors of PKA in the heart. The physiological and pathophysiological relevance of PKIα has not been studied. Hypothesis: PKIα inhibits PKA activity in normal and stressed (post-myocardial infarction (MI)) hearts. Methods: PKIα knockout (KO) and c57bl/6 control (CTR) mice were used to test if PKIα affected cardiac β-adrenergic response and if played a role in post-MI hearts. Results: Protein abundance of PKIα was significantly increased in failing human and post-MI mouse ventricular tissue. The knockout of PKIα in mice did not affect the expression of the other two PKI isoforms. Nor did it change the expression of PKA regulatory and catalytic subunits. PKIα KO mice did not show alterations in basal cardiac morphology, function and life span of mice. Intra-LV hemodynamic measurements in response to different doses of isoproterenol showed that the loss of PKIα sensitizes the heart in response to isoproterenol (ISO) with a lower EC50 and the maximum response was increased more in KO mice than in control mice. ISO (10nM) increased myocyte contraction and Ca2+ transient amplitudes more in KO myocytes than control myocytes though 100nM ISO increased myocyte contraction and Ca2+ transients amplitude to the same. At the ISO concentration of 10nM, ISO increased more phosphorylation of the Ser16 site (PKA site) on phospholamban. In post-MI animals, the loss of PKIα enhances cardiac function at 1 week after MI but caused more myocardial infarction and functional depression at 8 weeks after MI. Conclusions: PKIα is an important regulator of cardiac β-adrenergic responses by antagonizing PKA. This mechanism could be protective to avoid β-adrenergic overstimulation, especially in post-MI patients and animal models.
An Abnormal Serum Concentration of High-sensitivity Cardiac Troponin T is Associated with Progression of Left Ventricular Remodeling in Hypertrophic Cardiomyopathy
Authors: Kubo Toru, Hirota Takayoshi, Hamada Tomoyuki, Noguchi Tatsuya, Tanioka Katsutoshi, Yamasaki Naohito, Sugiura Tetsuro, Kitaoka Hiroaki
Journal: Circulation (2016)
Paternity After Treatment for Testicular Germ Cell Cancer: A Danish Nationwide Population-Based Cohort Study
Authors: Mikkel Bandak, Allan Jensen, Christian Dehlendorff, Jakob Lauritsen, Michael Kreiberg, Thomas Wagner, Josephine Rosenvilde, Gedske Daugaard
Journal: JNCI Journal of the National Cancer Institute (2021)

Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment.Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register.We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities.The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men.
Abstract SY37-01: Genomic instability and hypoxia as co-drivers of prostate cancer aggression
Authors: Robert G. Bristow
Journal: Cancer Research (2021)

Abstract Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Sub-regions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in prostate cancer. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signalling and chromosome instability. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p &amp;lt; 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p &amp;lt; 0.005) specifically in chronic hypoxic cells with PTEN loss. Hypoxic suppression of homologous recombination represents a "contextual lethal" vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Additional mechanistic studies using hTERT-immortalized, primary prostate epithelial cells isogenic for c-MYC, BRCA2, or TP53/RB (SV40-transduced) were studied as to the relationship between hypoxia, inherent versus acquired genetic instability and DNA repair capacity in-vitro and in-situ. Chronic hypoxia (20 generation doublings at 0.2% O2) was sufficient to drive increased copy number alterations (CNAs) in selected clones by up to 30% in TP53/RB null cells. This finding is now being quantitated with a clonal evolution model and genotype-phenotype associations are being validated using functional transformation and invasion assays. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to prostate and other cancers and also characterise the role of hypoxia in driving early metastatic spread. Supported by core funding from Cancer Research UK Manchester Institute and grants within the Cancer Research UK Manchester RadNet Unit, NIHR Manchester Biomedical Research Centre and a Prostate Cancer UK-Movember Centre of Excellence award. Citation Format: Robert G. Bristow. Genomic instability and hypoxia as co-drivers of prostate cancer aggression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY37-01.
The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in the Prevention of Venous Thromboembolism after Elective Hip or Knee Replacement Surgery
Authors: Scott D. Berkowitz, Keith A A Fox, Stephan Schmidt, Jeffrey I Weitz, Dirk Garmann, Dagmar Kubitza, Wolfgang Mueck, Gary Peters, Isabel Reinecke, Alexander Solms, Theodore E Spiro, Xiaoyu Yan, Liping Zhang, Stefan Willmann
Journal: Blood (2017)
糖尿病:プロテクチンDXはミオカイン-肝血糖調節経路の活性化によりインスリン抵抗性を改善する | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: White Phillip J, St-Pierre Philippe, Charbonneau Alexandre, Mitchell Patricia L, St-Amand Emmanuelle, Marcotte Bruno, Marette Andre
Journal: Nature Medicine (2014)