tbuckley/cabot-search huggingface dataset:
Response to: ‘Comment on editorial ‘Pathogenic effector functions of ACPA: where do we stand’’ by Holmdahl
Authors: René Toes, David S Pisetsky
Journal: Annals of the Rheumatic Diseases (2019)

Dr Holmdahl 1 on our editorial entitled 'Pathogenic effector functions of ACPA: where do we stand?' 2 and thank him for the additional information.We fully agree with him about the importance of accuracy, reliability and reproducibility of data published in the literature.Our editorial, however, was based on information available in scientific journals and focused on methodological considerations in determining the role of anti-citrullinated protein antibodies (ACPAs) in the pathogenesis of rheumatoid arthritis.4][5][6][7] We believe that these issues can best be handled in venues in which the authors can respond and provide their own perspective.
Abstract 2956: Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase
Authors: David Gordon, Kelli Goss, Stacia Koppenhafer
Journal: Cancer Research (2019)

Abstract Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The treatment of Ewing sarcoma has changed very little in the past two decades and novel treatment approaches are needed. We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate limiting enzyme in the synthesis of deoxyribonucleotides. We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine. The ATR-CHK1 pathway, from a mechanistic standpoint, regulates multiple stages of the cell cycle, including S-phase, the G2/M transition, and M phase. In the current work, we used cell synchronization to identify that the inhibition of CHK1 in S-phase cells results in premature entry into mitosis and cell death. Similarly, the inhibition of ATR serine/threonine kinase (ATR), the upstream activator of CHK1, also causes Ewing sarcoma cells to inappropriately enter mitosis. Moreover, we have found in Ewing sarcoma cells that this aberrant entry into mitosis is mediated, in part, by cyclin dependent kinase 1 (CDK1). In addition, activation of CDK1 by inhibiting the WEE1 kinase with AZD1775 also results in entry into mitosis and cell death in Ewing sarcoma cells. Currently, ongoing work is focused on the in vivo testing of gemcitabine in combination with CHK1 and WEE1 inhibitors as a novel therapeutic approach for the treatment of Ewing sarcoma. Citation Format: David Gordon, Kelli Goss, Stacia Koppenhafer. Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2956.
Abstract 36: Application of patients derived organoids as co-clinical model
Authors: Young-Won Cho, Hwang-Phill Kim, Dong Wook Min, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim
Journal: Cancer Research (2019)

Abstract Organoids are known to best in vitro model system which mostly mimic genetic, phenotypic feature of its origin. And it is expected and suitable to variable disease modeling and study. For cancer modeling using organoids as co-clinical model, our group derived organoids from 40 colorectal tumor including lymph node, terminal ileum metastatic tumor and ascites. Whole exome sequencing of matched tumor organoids and tissues was performed and their somatic mutation concordance was analyzed. As a results, Organoids reflect their genetic statues of the original tumor tissue and their phenotypic features are maintained. In order to prove the appliance of these organoids as a co-clinical model, clinical drugs on colorectal cancer such as 5-Fluorouracil, oxaliplatin, SN38 and cetuximab were tested. The drug results reflected the actual clinical outcome of the corresponding patients. To find the precise drug treatment option for conventional chemo-refractory patients, we performed 134 anti-cancer drug library screening. Organoids with specific mutations were sensitive to drugs which target these corresponding mutations. For instance, organoid with RNF43 mutation was sensitive to porcupine inhibitor which suppresses auto- and paracrine WNT- driven growth. In conclusion, we suggest that patient derived organoids can be applied in cancer treatment as a co-clinical model, due to their highly correlated genetic information and drug sensitivity with those of the patients themselves. Citation Format: Young-Won Cho, Hwang-Phill Kim, Dong Wook Min, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim. Application of patients derived organoids as co-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 36.
Hybrid management of perforated gangrenous gallbladder
Authors: Iman Andalib, Daniel Kats, Amy Tyberg, Haroon Shahid, Susannah S. Wise, Avik Sarkar, Michel Kahaleh
Journal: Endoscopy (2019)

A 72-year-old man, with a history of myelodysplastic syndrome with chemotherapy and previous choledocholithiasis treated by endoscopic extraction, presented with acute cholecystitis. Because of his co-morbidities, he was not a candidate for surgery. Therefore, he underwent successful endoscopic ultrasound (EUS)-guided transduodenal gallbladder drainage using a lumen-apposing metal stent (LAMS). The patient’s clinical status worsened, with peritoneal signs 2 days later. Abdominal computed tomography (CT) was done which showed the LAMS in place, and a possibly perforated gangrenous gallbladder.
Особливості гістоструктури стравоходу і шлунка при запальних та ерозивно-виразкових захворюваннях верхнього відділу шлунково-кишкового тракту, асоційованих з кандидозом слизових оболонок
Authors: Yu.A. Gaidar, L.M. Mosiychuk, I.V. Kushnirenko, N.Yu. Oshmyanska
Journal: GASTROENTEROLOGY (2013)

Обстежено 84 хворих на запальні та ерозивно-виразкові хвороби езофагогастральної зони, 72 з них — з кандидозною інфекцією.Встановлено, що характерними гістологічними ознаками є дискератоз слизової оболонки стравоходу та запалення з більш тяжким його ступенем, порівняно з пацієнтами без кандидозу, при цьому всі випадки езофагіту II ступеня виявлено у хворих із глибоким кандидозом стравоходу.Поширення інфекції у стравохід і/або шлунок відбувається на тлі зниження товщини базального епітелію при вірогідному збільшенні співвідношення середньої його висоти до загальної висоти епітелію, а також супроводжується запальними та атрофічними змінами у слизовій оболонці фундального відділу шлунка, які є характерними для переважної більшості пацієнтів.
Recurrence rate in colorectal adenocarcinoma patients receiving adjuvant capecitabine monotherapy: do the number of chemotherapy cycles and relative dose intensity of the drug play a role?
Authors: J. Sgouros, N. Spathas, S. Gkoura, S. Kanellopoulou, D. Lambropoulou, M. Belechri, N. Miaris, D. Kozompoli, M. Tsoukra, G. Stamoulis, G. Aravantinos, E. Samantas
Journal: Annals of Oncology (2019)
Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess
Authors: Yasir S. Elhassan, Fares Alahdab, Alessandro Prete, Danae A. Delivanis, Aakanksha Khanna, Larry Prokop, Mohammad H. Murad, Michael W. O'Reilly, Wiebke Arlt, Irina Bancos
Journal: Annals of Internal Medicine (2019)

Background: Adrenal incidentalomas are mostly benign nonfunctioning adrenal tumors (NFATs) or adenomas causing mild autonomous cortisol excess (MACE), but their natural history is unclear. Purpose: To summarize the follow-up data of adults with NFAT or MACE to determine the proportions of tumor growth, malignant transformation, and incident changes in hormone function; the prevalence of incident cardiometabolic comorbid conditions; and mortality. Data Sources: MEDLINE, Embase, Cochrane, and Scopus (January 1990 to February 2019) and bibliographies of identified articles, without language restriction. Study Selection: Studies that included 20 or more conservatively managed patients with NFAT or MACE and reported outcomes at baseline and after at least 12 months of follow-up. Data Extraction: Pairs of reviewers extracted outcomes and assessed methodological quality. Data Synthesis: Thirty-two studies reported outcomes of 4121 patients with NFAT or MACE, 61.5% of whom were women; the mean age was 60.2 years, and mean follow-up was 50.2 months. Mean tumor growth was 2 mm over 52.8 months. Clinically significant tumor enlargement (≥10 mm) occurred in 2.5% of patients, and none developed adrenal cancer. Clinically overt hormone excess was unlikely to develop (<0.1%) in patients with NFAT or MACE. Only 4.3% of patients with NFAT developed MACE, and preexisting MACE was unlikely to resolve (<0.1%). Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent (60.0%, 42.0%, 33.7%, and 18.1% of patients, respectively) and were more likely to develop and worsen in MACE than NFAT. New cardiovascular events were more prevalent in MACE (15.5%) than NFAT (6.4%). Mortality was 11.2% and was similar between NFAT and MACE. Limitation: Evidence was scarce, and definitions of MACE and comorbid conditions were heterogeneous. Conclusion: During follow-up, NFAT and MACE do not show clinically relevant changes in size or hormonal function, but they may carry an increased risk for cardiometabolic comorbid conditions. Primary Funding Source: None.
Abstract 3046: Targeting N-myristoylation in B cell lymphomas as a therapeutic strategy
Authors: John R. Mackey, Erwan Beauchamp, Megan C. Yap, Aishwarya Iyer, Maneka A. Perinpanayagam, Krista M. Vincent, Abass M. Al-Momany, Ryan J. Heit, Jacky Y. Sim, Raymond Lai, Wei-feng Dong, Manikandan Lakshmanan, Anandhkumar Raju, Vinay Tergaonkar, Soo Yong Tan, Soon Thye Lim, Lynne M. Postovit, Kevin D. Read, David W. Gray, Paul G. Wyatt, Luc G. Berthiaume
Journal: Cancer Research (2019)

Abstract Treatment of aggressive lymphoma is toxic, expensive, and a substantial proportion of patients relapse and die. There is an urgent need for more effective treatments. Myristoylation is required for biological activity of &amp;gt;200 intracellular proteins. N-myristoyltransferases (NMTs) transfer the fatty acid myristate to N-terminal glycine residue; there are two isoforms, NMT1 and 2. Since they are critical to intracellular signaling, NMTs are potential anti-cancer targets. We tested a novel potent pan-NMT inhibitor, PCLX-001, in B cell lymphoma cell lines. In vitro assays included cell viability, immunoblotting, and metabolic labeling of lymphoma cell lines. Immunohistochemistry was performed on formalin fixed paraffin embedded lymphoma specimens from patients. In vivo experiments included cell line derived murine xenografts and a patient derived mouse xenograft treated with increasing concentrations of PCLX-001. PCLX-001 selectively killed lymphoma cells, while sparing normal cells in vitro and in 3 mouse xenograft models, eradicating tumors in two of these models including a patient-derived xenograft from a R-CHOP refractory lymphoma patient. While NMT2 is overexpressed in some cancers, loss of NMT2 expression is common in numerous cancers and occurs at the highest prevalence in lymphomas, where it is independently linked to a worse prognosis. This NMT2 suppression occurred through epigenetic mechanisms and may account for lymphoma sensitivity to NMT inhibition. The global myristoylation of lymphoma cell proteins, including that of the protein tyrosine kinase oncogene Src, is profoundly inhibited by PCLX-001. Loss of Src myristoylation is accompanied by loss of Src activity and may account for loss of prosurvival signals causing lymphoma cell death. Targeting NMT2 deficient B cell lymphoma with a pan-NMT inhibitor suppresses the residual NMT1 function provides a novel, selective, and effective therapeutic strategy. Citation Format: John R. Mackey, Erwan Beauchamp, Megan C. Yap, Aishwarya Iyer, Maneka A. Perinpanayagam, Krista M. Vincent, Abass M. Al-Momany, Ryan J. Heit, Jacky Y. Sim, Raymond Lai, Wei-feng Dong, Manikandan Lakshmanan, Anandhkumar Raju, Vinay Tergaonkar, Soo Yong Tan, Soon Thye Lim, Lynne M. Postovit, Kevin D. Read, David W. Gray, Paul G. Wyatt, Luc G. Berthiaume. Targeting N-myristoylation in B cell lymphomas as a therapeutic strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3046.
Combined Effects of Alcohol and Metabolic Disorders in Patients With Chronic Liver Disease
Authors: Fredrik Åberg, Pauli Puukka, Veikko Salomaa, Satu Männistö, Annamari Lundqvist, Liisa Valsta, Markus Perola, Antti Jula, Martti Färkkilä
Journal: Clinical Gastroenterology and Hepatology (2019)
Abstract LB-205: A lipoplex-based mRNA nanovaccine for cancer immunotherapy
Authors: Zhang Hongxia, You Xinru, Wang Xiaojuan, Wang Zining, Xu Feifei, Wu Jun, Xia Xiaojun
Journal: Cancer Research (2019)

Abstract Intracellular delivery of messenger RNA (mRNA)-based cancer vaccines have shown great potential to activate antitumor immune response for cancer prevention and therapy. In vivo delivery efficiency of mRNA has been greatly improved by various nucleotide chemical modifications and nanovector formulations, but the efficacy of mRNA vaccine remains unsatisfied. Here, we report a lipoplex-based mRNA nanovaccine that can markedly improve mRNA delivery in antigen presenting cells, activate T cell response, and induce robust antitumor immunity. The nanovaccine formulation contains three components: cationic polymer/lipid(poly(amidoamine)/alkylene oxide), DSPE-PEG2000, and epitope-encoding mRNA. With appropriate ratio, the optimized nanovaccine show effective mRNA delivery in dendritic cells, and strongly active antigen-specific immune response in vitro and in vivo. The mRNA@lipoplex nanovaccine enhanced mRNA uptake by dendritic cells, and significantly increased T cell activation reflected by IL-2 and IFN-γsecretion in an in vitro antigen presentation assay. Besides enhancing cross-presentation, nanoparticle itself can promote the expression of inflammatory cytokines such as IL-12 via stimulating NF-κB signal pathway in dendritic cells. In a tumor prevention setting, mRNA@lipoplex nanovaccine produced strong CD8+ T cell activation and great efficacy in preventing tumor development. Furthermore, treatment of established B16 and B16-OVA melanoma and MC38-OVA colon tumors with nanovaccine containing mRNA encoding cancer-associated antigen resulted in great therapeutic efficacy and prolonged survival. Re-challenge of tumor-free mice with MC38-OVA cells led to complete tumor rejection, suggesting long-term antitumor memory. In conclusion, our work presents a new means to deliver mRNA cancer vaccine, which in principle may be applied for immunotherapy for a wide range of tumor types. Citation Format: Zhang Hongxia, You Xinru, Wang Xiaojuan, Wang Zining, Xu Feifei, Wu Jun, Xia Xiaojun. A lipoplex-based mRNA nanovaccine for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-205.
Abstract 3961: Peripheral Vascular Endothelial Function Remains Impaired in Heart Transplant Recipients
Authors: Sandra Mandic, Daniel Kim, Wayne Tymchak, Dylan Taylor, H A Quinney, Ken Riess, Mark J Haykowsky
Journal: Circulation (2006)

Background and Rationale: Individuals with heart failure (HF) have severely reduced peak aerobic power (VO2peak) and abnormal peripheral vascular endothelial function. Previous investigations have ...
Abstract 73: Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib
Authors: Jiajia Gu, Xia He, Nupam P. Mahajan, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun
Journal: Cancer Research (2019)

Abstract The approval of osimertinib (AZD9291) as a third generation EGFR inhibitor for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790M mutation (second-line) have generated tremendous benefits to these NSLCL patients. However, the unavoidable development of acquired resistance to osimertinib limits the long-term benefits of patients. Thus, effective treatment options are urgently needed. Activated Cdc42-associated kinase 1 or ACK1 (also named as TNK2) is a non-receptor tyrosine kinase with oncogenic function. Although ACK1 gene is amplified in lung squamous cell carcinoma, its involvement in lung cancer including regulation of drug resistance has largely not been investigated. We found that inhibition of ACK1 with (R)-9bMS, a specific ACK1 inhibitor, synergized with AZD9291 in inhibiting the growth of EGFR mutant NSCLC cell lines. Similar results were also generated when ACK1 is genetically inhibited through transient shRNA gene knockdown. The combination of AZD9291 and (R)-9bMS enhanced induction of apoptosis as evaluated by detecting annexin V-positive cells with flow cytometry and PARP cleavage using Western blotting. In an in vitro long-term resistance delay assay, the combination of (R)-9bMS and AZD9291 clearly prevented the emergence of AZD9291-resistance as evaluating resistant cell colony formation and growth. Beyond the combination was also effective in inhibiting the growth of EGFR mutant NSCLC cell lines with acquired resistance to AZD9291. In some resistant cell lines, the combinations induced senescence in addition to induction of apoptosis. These preliminary findings suggest that ACK1 inhibition might be a potential and innovative strategy for preventing and overcoming AZD9291 acquired resistance. Hence further in vivo and mechanistic studies are warranted. (This work was supported by the NIH/NCI R01 CA223220 and Winship lung cancer pilot award to SYS; NIH/NCI R01 CA208258, Bankhead Coley Award-6BC08 and Prostate Cancer Foundation (PCF) Challenge award-17CHAL06 to NPM). Citation Format: Jiajia Gu, Xia He, Nupam P. Mahajan, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun. Inhibition of ACK1 delays and overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 73.
Abstract 3946: Tumor checkpoint inhibitor profiling for an optimal clinical response
Authors: Rachana R. Maniyar, Sanjukta Chakraborty, Ghada Ben Rahoma, John J. Degliuomini, Marc Wallack, Jan Geliebter, Raj K. Tiwari
Journal: Cancer Research (2019)

Abstract The last three decades have seen a steady rise in melanoma, the most aggressive form of skin cancer. The discovery of checkpoint inhibitors has revolutionized the treatment landscape for melanoma; anti-CTLA4 and anti-PD1 showing great successes in clinic. While checkpoint molecules and co-stimulatory molecules are traditionally present on cells involved in immune activation, mounting evidence suggests that tumor cells also express these molecules. Our laboratory has characterized five patient-derived melanoma cell lines, MEL-2, MEL-V, 3MM, KFM, and GLM-2 and screened them for the expression of a comprehensive list of 29 co-stimulatory and co-inhibitory molecules compared to normal adult melanocytes. We see a differential mRNA expression of many of these immune-regulatory molecules, including BTLA, HVEM, CD160, CD226 and TIM1. Western blots and immunofluorescence confirmed the presence of these molecules at the protein level. A flow cytometry analysis demonstrated that BTLA, HVEM, CD160, TIM1 and CD226 are present on the membrane of these patient derived melanoma cells; implying that they are capable of engaging their respective ligands and exerting a functional role in immunomodulation. These findings were additionally validated in melanoma tissues, obtained from patients, by immunohistochemistry. Interestingly, treatment of MEL-2, MEL-V, KFM and GLM-2, our BRAFV600E containing patient derived cells, with BRAFV600E inhibitor PLX4032 led to the upregulation of these molecules. This upregulation was coupled with an increase in transcription factor MITF, a binding site for which is present in the promoter region of all the upregulated molecules. Co-culture experiments with immune cells, demonstrate a modulatory role played by the HVEM/BTLA/CD160 axis molecules that are present on tumor cells. The presence of these additional immune-regulatory molecules signify the existence of a robust tolerance mechanism induced by these checkpoint inhibitors. Our studies underscore the importance of characterizing tumor profiles to enable the selection of an optimal treatment regimen combining targeted small molecule inhibitors, and checkpoint inhibitors to maximize T cell killing, and tumor clearance. Citation Format: Rachana R. Maniyar, Sanjukta Chakraborty, Ghada Ben Rahoma, John J. Degliuomini, Marc Wallack, Jan Geliebter, Raj K. Tiwari. Tumor checkpoint inhibitor profiling for an optimal clinical response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3946.
Quantifying the impact of genes on body mass index during the obesity epidemic: longitudinal findings from the HUNT Study
Authors: Maria Brandkvist, Johan Håkon Bjørngaard, Rønnaug Astri Ødegård, Bjørn Olav Åsvold, Erik R Sund, Gunnhild Åberge Vie
Journal: BMJ (2019)

To study the trajectories of body mass index (BMI) in Norway over five decades and to assess the differential influence of the obesogenic environment on BMI according to genetic predisposition.Longitudinal study.General population of Nord-Trøndelag County, Norway.118 959 people aged 13-80 years who participated in a longitudinal population based health study (Nord-Trøndelag Health Study, HUNT), of whom 67 305 were included in analyses of association between genetic predisposition and BMI.BMI.Obesity increased in Norway starting between the mid-1980s and mid-1990s and, compared with older birth cohorts, those born after 1970 had a substantially higher BMI already in young adulthood. BMI differed substantially between the highest and lowest fifths of genetic susceptibility for all ages at each decade, and the difference increased gradually from the 1960s to the 2000s. For 35 year old men, the most genetically predisposed had 1.20 kg/m2 (95% confidence interval 1.03 to 1.37 kg/m2) higher BMI than those who were least genetically predisposed in the 1960s compared with 2.09 kg/m2 (1.90 to 2.27 kg/m2) in the 2000s. For women of the same age, the corresponding differences in BMI were 1.77 kg/m2 (1.56 to 1.97 kg/m2) and 2.58 kg/m2 (2.36 to 2.80 kg/m2).This study provides evidence that genetically predisposed people are at greater risk for higher BMI and that genetic predisposition interacts with the obesogenic environment resulting in higher BMI, as observed between the mid-1980s and mid-2000s. Regardless, BMI has increased for both genetically predisposed and non-predisposed people, implying that the environment remains the main contributor.