tbuckley/cabot-search huggingface dataset:
PS1366 TISSUE ENGINEERING OF AN ORTHOTOPIC HUMANIZED BONE-ORGAN AS A PLATFORM FOR PRECLINICAL MULTIPLE MYELOMA RESEARCH
Authors: A. Sanchez, J. McGovern, C. Lahr, M. Landgraf, A. Shafiee, F. Prósper, J.F. San Miguel, D. Hutmacher
Journal: HemaSphere (2019)

Background: Genetic heterogeneity in multiple myeloma (MM) affects not only the disease development but also therapeutic response and prognosis. Nowadays, karyotype and FISH are standard diagnostic tools for the detection of genetic aberrations in MM. However, comprehensive analysis of genome architecture, particularly structural variations (SVs), still remain a challenge. Aims: To study the genomic architecture of MM cells using a novel nanochannel technology based on optical mapping of high-molecular weight DNA in order to refine genomic variability in human MM. Methods: We analysed five samples of bone marrow aspirates from patients with newly diagnosed MM. High-molecular weight DNA was isolated from sorted MM cells, labelled by DLS chemistry and visualised by Saphyr optical system (BioNano Genomics). Created single molecules were de novo assembled into physical maps spanning whole genome based on known labelled specific motifs. After filtering of structural variants against the database of healthy controls, only rare de novo variants were analysed. Karyotype, FISH, and arrayCGH results were available for the enrolled patients and were compared to the results of optical mapping. Results: For all MM samples, the optical genome maps (480 Gbp) were assembled with an average effective coverage of 124X and aligned to a human reference genome (GRCh38). In our cohort, numerous copy number variations and large somatic SVs, including deletions, insertions, inversions, duplications and translocations, were identified (Table 1) with majority of SVs being deletions (∼60%). All genetic variants detected by arrayCGH were also confirmed by mapping. Additional SVs with novel intra- and inter-chromosomal translocations and copy number variants were found in all patients, not detected by FISH/arrayCGH. Regarding novel translocations, majority were intra-chromosomal (64%) within chromosomes 3, 4, 6, 14, 16, 17, and 18. Additional translocations (36%), detected only by mapping, involved unusual chromosomes in MM: t(2;8), t(3;6), t(3;12), t(6;8), t(6;17), t(8;9), and t(8;22). All samples carried novel SVs on chromosome 17, including two intra- (P1) and one inter-chromosomal translocations (P2), insertions in four (P2-P5) and deletions in two (P4-P5) patients. Although no IGH locus rearrangements were detected by standard methods, monosomy on chromosome 14 within IGH locus was observed in four samples (P2-P5) by mapping. The analyses of associations of SVs and affected genes with clinical characteristics are ongoing.Summary/Conclusion: A large spectrum of novel genomic rearrangements was detected in MM using next-generation mapping technology, showing a high potential of optical maps for refinement of genomic variability in human MM. Grant support: research grant Celgene, MZ ČR VES16–32339A, NV18–03–00500, MZ ČR – RVO (FNOl, 00098892)
Abstract 14384: Supplementation With Epa and With Dha Induces Similar Inflammatory Gene Expression Profiles in Human Whole Blood Cells: The Compared Study
Authors: Cécile Vors, Janie Allaire, Johanne Marin, Marie-Claude Lépine, Amélie Charest, André Tchernof, Patrick Couture, Benoit Lamarche
Journal: Circulation (2016)

Introduction: Low-grade inflammation is recognized as a key etiological factor in the development of CVD. Whether DHA and EPA have similar anti-inflammatory effects remains unclear, as most of the ...
Mechanobiology: Unraveling the Mechanobiology of the Immune System (Adv. Healthcare Mater. 4/2019)
Authors: Jeong‐Ki Kim, Yu Jung Shin, Leslie Jaesun Ha, Deok‐Ho Kim, Dong‐Hwee Kim
Journal: Advanced Healthcare Materials (2019)

Immune response is an active and essential process for the maintenance of biological homeostasis in complex tissues. Understanding multifaceted immune regulatory systems at the cellular level is necessary for diagnosis of the disease and the development of new and improved therapeutic treatments. The review in article number 1801332 by Dong-Hwee Kim, Deok-Ho Kim, and co-workers provides the cell-level mechanobiological interpretation of immune responses.
Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure
Authors: Andras Iring, Young-June Jin, Julián Albarrán-Juárez, Mauro Siragusa, ShengPeng Wang, Péter T. Dancs, Akiko Nakayama, Sarah Tonack, Min Chen, Carsten Künne, Anna M. Sokol, Stefan Günther, Alfredo Martínez, Ingrid Fleming, Nina Wettschureck, Johannes Graumann, Lee S. Weinstein, Stefan Offermanns
Journal: Journal of Clinical Investigation (2019)

Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.
AB1137 QUANTIFYING KNEE JOINT EFFUSIONS WITH CLINICAL TESTS, MUSCULOSKELETAL ULTRASOUND AND SYNOVIAL FLUID ASPIRATION: A PROSPECTIVE COHORT STUDY
Authors: Thilinie De Silva, Chris Pham, Adam Rischin, Kim Le Marshall, Sara Vogrin, Albert Leung, Keith Lim
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Aspiration of knee joint effusions is an integral diagnostic and therapeutic intervention in many rheumatologic diseases. Clinical examination has traditionally involved tests including the "patella tap" or "bulge test". The accuracy of these tests for determining effusion presence and size is not well established. Musculoskeletal ultrasound (MUS) is considered better for identification and quantification of knee effusions. <h3>Objectives</h3> To investigate the correlation between both clinical examination and MUS to aspirated knee effusion volume. <h3>Methods</h3> We performed a prospective cohort study of 37 osteoarthritis patients with symptomatic knee effusions. Clinical assessment with patella tap, bulge test and knee circumference measurement were carried out. MUS was used to measure effusion depth in the suprapatellar, lateral and medial parapatellar views. All knee effusion aspirations were performed by the same experienced clinician using a consistent, lateral approach. Linear regression analysis was used to assess correlations between clinical tests, MUS and aspiration volume. <h3>Results</h3> In patients with &gt;3ml of fluid aspirated, patella tap and bulge test were positive in 67% and 80% respectively. The positive predictive value for bulge test was 80%. Where larger volumes were aspirated (i.e. &gt;10ml), patella tap and bulge test were only positive in 52% and 65% respectively. There was a significant correlation between the measured circumference of the index and non-index knee and aspiration of fluid (coefficient=5.6, p=0.007). The relationship between fluid depth on MUS and aspirated volume showed a trend towards statistical significance, with a depth of 1mm equating to 1.57 ml of fluid (coefficient=1.57, p=0.06). <h3>Conclusion</h3> This pilot study demonstrates that a positive patella tap or bulge test is moderately predictive of knee effusion volume. However, this association is weaker when larger knee effusions are present. MUS showed promise at accurately predicting knee effusion volume. A larger study is underway to assess this relationship further. <h3>Disclosure of Interests</h3> Thilinie De Silva: None declared, Chris Pham: None declared, Adam Rischin: None declared, Kim Le Marshall: None declared, Sara Vogrin: None declared, Albert Leung: None declared, Keith Lim Consultant for: Advisor for role of hepatitis and TB in Cimzia, UCB, Speakers bureau: Role of biological in pregnancy UCB
PF421 PLANNED PREGNANCY IN FEMALE PATIENTS WITH CHRONIC MYELOID LEUKEMIA RECEIVING TYROSINE KINASE INHIBITOR THERAPY
Authors: X. Dou, Y. Qin, X. Huang, Q. Jiang
Journal: HemaSphere (2019)

Background: Pregnancy has become an important issue in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI). Female patients with CML who wish to conceive are currently advised to discontinue TKI before conception due to the recognized teratogenic effects of TKI. However, it is not known what the ideal degree and duration of response a female patient should achieve before stopping TKI‐therapy for pregnancy. Concrete infant outcomes for female patients who discontinued TKI‐therapy immediately once pregnancy was confirmed are also lacking. Aims: To explore disease and fetal outcomes of planned pregnancy in female patients with CML on tyrosine TKI therapy. Methods: Data of female patients with CML proceeding with a planned pregnancy were retrospectively reviewed. Results: A total of 17 female CML patients who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, patients had received TKI‐therapy for a median of 49 months (range, 6–102 months), 6 were in MMR, 2 in MR 4 , and 9 in MR 4.5 . TKI‐therapy was discontinued at a median of 6 weeks (range, 2–15 weeks) before conception in 4 patients and at a median gestational age of 4 weeks (range, 2–5 weeks) after determination of pregnancy in 13 patients. Apart from one patient who suffered a spontaneous abortion, 16 patients delivered uneventfully at full term. A total of 10 patients lost MMR at a median of 3 months (range, 1–9 months) after stopping TKI; 8 patients lost MR 2 at 4 months (range, 2–7 months) and 3 lost complete hematological response (CHR) at 3 months (range, 3–4 months) after TKI cessation. None of the patients progressed to an advanced phase. Log‐rank analyses showed achievement of MR 4 (p = 0.030), MR 4.5 (p = 0.031), CCyR (p = 0.049) or MMR duration (p = 0.040) ≥3.5 years were significantly associated with longer MMR‐failure free survival. Each of the 10 patients losing MMR during pregnancy regained MMR at a median of 4 months (range, 2–7 months) after resuming TKI‐therapy, and 1 patient who maintained MR 4.5 during pregnancy remained off treatment at 6 months after delivery. All 16 babies that were successfully delivered have continued normal growth and development during a median follow‐up of 19 months (range, 7–78 months). Summary/Conclusion: Planned pregnancy might be safe and practicable in female patients with CML on TKI‐therapy. Achieving deep molecular response and importantly MMR duration ≥3.5 years before conception were significantly associated with maintaining MMR during pregnancy. image
Drugs for Heart Disease With Rare Cause
Authors: Feyza Sancar
Journal: JAMA (2019)

The FDA recently approved 2 drugs for adults with cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR), a rare and life-threatening disease. The oral medications, tafamidis meglumine and tafamidis, are the first to receive agency approval for this indication.
Response to Comment on Barbour and Feig. Metformin for Gestational Diabetes Mellitus: Progeny, Perspective, and a Personalized Approach. Diabetes Care 2019;42:396–399
Authors: Linda A. Barbour, Denice S. Feig
Journal: Diabetes Care (2019)

We appreciate Dr. Rowan’s thoughtful comments (1) on our article (2), as her comments make a number of important points. As she notes, there are conflicting mouse data with respect to the effect of metformin. Furthermore, it is difficult to extrapolate mouse studies to humans given that there are marked differences in placentation and oxidative/proliferative pathways, the early postnatal period may have stronger developmental effects than later pregnancy, and mice are typically born with only 2–3% fat compared with 6–14% fat in humans. However, in one of the mouse studies Dr. Rowan cited, prenatal metformin did lead to increased weight gain, mesenteric fat, and liver weight after a high-fat diet, and males showed glucose intolerance (3).

Dr. …
PF613 CLINICAL UTILITY OF [18F]FLORBETABEN PET/CT SCAN FOR IMAGING AMYLOIDOSIS IN MULTIPLE MYELOMA PATIENTS
Authors: J.‐C. Jo, M. Seo, Y.S. Choi, Y.J. Lee, S.H. Park, H.J. Cha, S.H. Park
Journal: HemaSphere (2019)

Background: [ 18 F]Florbetaben is a positron emission tomography (PET) tracer that specifically binds to amyloid beta‐pleated structure. Diagnosis of immunoglobulin light‐chain amyloidosis in patients with multiple myeloma (MM) is clinically important to manage symptoms and signs associated with amlyoidosis. Aims: We aimed to evaluate the feasibility of [ 18 F]Florbetaben PET for detecting amyloid deposits in MM patients and to explore the most optimal method for PET analysis. Methods: Fourteen patients with multiple myeloma were prospectively enrolled (6 patients with amyloidosis and 8 controls) between Aug 2018 and Nov 2018. After injection of 300 MBq of [ 18 F]Florbetaben, dynamic imaging of the kidneys was acquired for 20 minutes. Time‐activity curve was generated by using a region of interest placed over the kidney and retention index (RI) was obtained. At 90 minutes post‐injection, PET image was acquired, with a scan field from the vertex to mid‐thigh. All images were assessed both qualitatively and quantitatively. Comparison between amyloidosis and non‐amyloidosis groups was performed, regarding SUVmax, SUVmean, and SUV ratio (SUVR = tissue of interest/reference region), which were obtained from both sphere and manually drawn volumes of interest (VOI). Amyloid deposition was confirmed according to international consensus guidelines. Results: All patients in the control group did not show any abnormal amyloid uptake on 18F‐Florbetaben PET/CT (0/8), while those in the amyloid group had amyloid positive findings in more than one organ (6/6, 100%). Among 15 organs confirmed to have amyloidosis involvement prior to PET/CT, 9 were positive on 18F‐Florbetaben PET/CT. The detection rates of amyloidosis involvement in the heart, stomach, and tongue were excellent (100%), whereas those of the liver, esophagus, and colon were poor. 18F‐Florbetaben PET/CT found 12 unexpected abnormal amyloid uptakes in the tongue, thyroid, heart, lung, stomach, and spleen. Three of these 12 unexpected uptakes were later clinically determined to be amyloidosis (1 tongue, 1 heart, and 1 lung). Summary/Conclusion: [ 18 F]Florbetaben PET can be one of the tool to detect systemic amyloid deposits in MM patients, especially in the heart, stomach, and tongue.
Pharmacological targeting of CDK9 in cardiac hypertrophy
Authors: Vladimír Kryštof, Ivo Chamrád, Radek Jorda,, Jiří Kohoutek
Journal: Medicinal Research Reviews (2009)

Abstract Cardiac hypertrophy allows the heart to adapt to workload, but persistent or unphysiological stimulus can result in pump failure. Cardiac hypertrophy is characterized by an increase in the size of differentiated cardiac myocytes. At the molecular level, growth of cells is linked to intensive transcription and translation. Several cyclin‐dependent kinases (CDKs) have been identified as principal regulators of transcription, and among these CDK9 is directly associated with cardiac hypertrophy. CDK9 phosphorylates the C ‐terminal domain of RNA polymerase II and thus stimulates the elongation phase of transcription. Chronic activation of CDK9 causes not only cardiac myocyte enlargement but also confers predisposition to heart failure. Due to the long interest of molecular oncologists and medicinal chemists in CDKs as potential targets of anticancer drugs, a portfolio of small‐molecule inhibitors of CDK9 is available. Recent determination of CDK9's crystal structure now allows the development of selective inhibitors and their further optimization in terms of biochemical potency and selectivity. CDK9 may therefore constitute a novel target for drugs against cardiac hypertrophy. © 2009 Wiley Periodicals, Inc. Med Res Rev 30, No. 4, 646–666, 2010
THU0352 THE ROLE OF PRURITOGENIC MEDIATORS IN DERMATOMYOSITIS RELATED ITCH
Authors: Anett Vincze, Erika Herczeg-Lisztes, Katalin Szabó, Melinda Nagy-Vincze, Tamás Bíró, Katalin Dankó, István Balázs Tóth, Zoltán Griger
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Pruritus is a common symptom in systemic autoimmune diseases like dermatomyositis (DM). Recent researches have indicated that interleukin-31 (IL-31), IL-33, IL-6, or inflammatory cytokines, such as tumor necrosis factor (TNFα), peroxisome proliferator-activated receptor γ (PPARγ) and ion channels belonging to the transient receptor potential (TRP) family are involved in pruriception. <h3>Objectives</h3> We examined targeted gene expression analysis of lesional versus non-lesional skin samples of patients affected with active DM. We looked for correlations between the examined pruriceptive signaling molecules, disease activity and itching sensation of DM patients. <h3>Methods</h3> Gene expression of TNFα, PPARγ, IL-33, IL-6 and TRPV channels in lesional DM skin was evaluated by RT-qPCR and was compared with non-lesional DM skin samples. Pruritus and disease activity of DM was evaluated by the 5-d itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 20.0 software. <h3>Results</h3> Skin samples of 17 active DM patients were analyzed. We could show, that itching index in DM was positively correlated with CDASI score with a correlation coefficient of 0.82 (p&lt;0.001). TNFα gene expression was significantly higher (34.87%) in lesional DM skin than non-lesional DM skin (p=0.03). The normalized TNFα mRNA expression was positively correlated with itch scale (R= 0.605, p=0.022) and its level was significantly higher in skin samples of patients with severe itch (itching score: 15-20) versus mild itch (itching score: 5-10) (2.02±0.38 vs. 1.12±0.20; p&lt;0.01). The level of PPARγ was decreased in lesional DM skin, but this was statistically not significant. The mRNA expression of normalized PPARγ was negatively correlated with itch scale (R= -0.618, p=0.019), and its level was significantly lower in skin samples of patients with severe itch versus mild itch (0.28±0.36 vs. 1.53±0.98; p=0.038). Lesional IL-6 mRNA levels were associated with CDASI activity score (R=0.619, p=0.018). The mRNA levels of TRPV1-4 channels were not associated with 5-D itch score, but normalized TRPV1 and TRPV4 mRNA expressions were positively correlated with CDASI damage score (R=0.699, p=0.008; R=0.789, p=0.001). Interestingly, itching sensation of DM patients was not correlated with IL-33 mRNA levels measured in skin samples. <h3>Conclusion</h3> Our results argue for that higher cutaneous disease activity generate pruritus. TNFα and PPARγ might play a determining, but opposite role in DM-associated itch. Furthermore IL-6, TRPV1 and TRPV4 channels might participate in pathomechanism of cutaneous manifestation of the disease. <h3>Disclosure of Interests:&nbsp;</h3>
Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1
Authors: Leilei Zhang, Jie Zhang, Zhiwei Ye, Yefim Manevich, Lauren E. Ball, Jennifer R. Bethard, Yu-Lin Jiang, Ann-Marie Broome, Annamarie C. Dalton, Gavin Y. Wang, Danyelle M. Townsend, Kenneth D. Tew
Journal: Cancer Research (2019)

ME-344 is a second-generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species and this initiated a nuclear erythroid factor 2-like 2 signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels, were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared with normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected, resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344. SIGNIFICANCE: A novel cytotoxic isoflavone is shown to inhibit heme oxygenase, a desirable yet elusive target that disrupts redox homeostasis causing cell death.
Enhancing financial protection under China’s social health insurance to achieve universal health coverage
Authors: Hai Fang, Karen Eggleston, Kara Hanson, Ming Wu
Journal: BMJ (2019)

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