tbuckley/cabot-search huggingface dataset:
Эволюция лечения кислотозависимой патологии
Authors: S.M. Tkach, A.E. Dorofeiev
Journal: GASTROENTEROLOGY (2020)

В статье рассмотрены основные этапы развития и совершенствования антисекреторной терапии, начиная от антацидов и заканчивая современными ингибиторами протонной помпы (ИПП). Сделан вывод, что в настоящее время основными препаратами для лечения кислотозависимой патологии являются ИПП, которые условно делятся на препараты I и II поколения. Препараты II поколения являются более эффективными и безопасными, поскольку меньше зависят от полиморфизма CYP2C19 и обладают наименьшим потенциалом побочных эффектов и межлекарственных взаимодействий. Наиболее безопасным ИПП для длительного лечения кислотозависимой патологии, особенно при необходимости приема других препаратов, является пантопразол.
Genetic Variation, Comparative Genomics, and the Diagnosis of Disease
Authors: Evan E Eichler
Journal: New England Journal of Medicine (2019)

Interview with Dr. Evan E. Eichler on genetic variation, comparative genomics, and the diagnosis of disease. (07:53)Download The genome is not akin to a string of fixed length. Many large segments of DNA may be present or absent — a major contributor to pathogenic genomic variation. New technologies in DNA sequencing are helping to uncover this type of variation, which often cannot be detected by standard DNA sequencing.
Abstract LB-273: Development of small molecule MYC inhibitors that impair tumor growth and enhance anti-PD1 immunotherapy
Authors: Huiying Han, Atul Jain, Vinay Sargar, Jonathan Anker, Rama Mishra, Gary Schiltz, Sarki A. Abdulkadir
Journal: Cancer Research (2019)

Abstract Small molecules MYC inhibitors that are efficacious and tolerated in vivo will provide invaluable chemical probes and potential therapeutic agents. We have used in silico screening coupled to a rapid in vivo screen in mice to develop a series of novel small molecule MYC inhibitors (MYCi) which engage MYC inside cells, disrupt MYC/MAX heterodimerization and inhibit MYC-regulated gene expression. The compounds enhanced MYC phosphorylation on threonine-58, leading to increased proteasome-mediated degradation of MYC. The initial lead, MYCi361, showed excellent in vivo anti-tumor efficacy in mice, inhibiting proliferation and inducing immunogenic cell death of tumor cells. MYCi361 treatment increased tumor infiltrating lymphocytes and induced tumor PD-L1 expression. Accordingly, treatment with MYCi361 sensitized tumors to anti-PD1 immunotherapy. MYCi361 however showed a narrow therapeutic index. We therefore undertook additional medicinal chemistry optimization, which yielded the related molecule, MYCi975, which combined in vivo efficacy with remarkable tolerability. These findings support the potential of small molecule MYC inhibitors as chemical probes and possible therapeutic leads. Citation Format: Huiying Han, Atul Jain, Vinay Sargar, Jonathan Anker, Rama Mishra, Gary Schiltz, Sarki A. Abdulkadir. Development of small molecule MYC inhibitors that impair tumor growth and enhance anti-PD1 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-273.
Baseline Frontoparietal Task-Related BOLD Activity as a Predictor of Improvement in Clinical Symptoms at 1-Year Follow-Up in Recent-Onset Psychosis
Authors: Jason Smucny, Tyler A. Lesh, Cameron S. Carter
Journal: American Journal of Psychiatry (2019)

The early course of illness in psychotic disorders is highly variable, and predictive biomarkers of treatment response have been lacking. Trial and error remains the basis for care in early psychosis, and poor outcomes are common. Early prediction of nonimprovement in response to treatment could help identify those who would benefit from alternative and/or supplemental interventions. The goal of this study was to evaluate the ability of functional MRI (fMRI) measures of cognitive control-related brain circuitry collected at baseline to predict symptomatic response in patients after 1 year.Patients with recent-onset (<2 years) psychotic disorders (N=82) in early psychosis specialty care were classified as improvers (>20% improvement in total score on the Brief Psychiatric Rating Scale [BPRS] at 1-year follow-up compared with baseline) or as nonimprovers. Behavioral (d' context) and fMRI (proactive control-associated activation in a priori frontoparietal regions of interest) measures of cognitive control were then evaluated on their ability to predict BPRS improvement using linear and logistic regression.Cognitive control-associated measures significantly predicted BPRS improvement and improver status, with 70% positive predictive value, 60% negative predictive value, and 66% accuracy. Only the fMRI-based measure (and not the behavioral measure) significantly predicted status.These results suggest that frontoparietal activation during cognitive control performance at baseline significantly predicts subsequent symptomatic improvement during early psychosis specialty care. Potential implications for fMRI-based personalized patient treatment are discussed.
Impact of consolidation therapy post autologous stem cell transplant in patients with light chain amyloidosis
Authors: Abdullah S. Al Saleh, M. Hasib Sidiqi, Surbhi Sidana, Eli Muchtar, Angela Dispenzieri, David Dingli, Martha Q. Lacy, Rahma M. Warsame, Wilson I. Gonsalves, Taxiarchis V. Kourelis, William J. Hogan, Suzanne R. Hayman, Robert C. Wolf, Prashant Kapoor, Francis K. Buadi, Shaji K. Kumar, Morie A. Gertz
Journal: American Journal of Hematology (2019)

The role of consolidation post autologous stem cell transplant in light chain amyloidosis is not well defined. We retrospectively identified patients who had light chain amyloidosis and underwent autologous stem cell transplant at the Mayo Clinic. Consolidation was defined as any treatment given after the day 100 evaluation post-transplant to maintain or deepen the response. We identified 471 patients, of whom 72 (15%) received consolidation. Patients receiving consolidation had more advanced disease (Mayo 2012 stage ≥II in 67% vs 52%, P = .02), and had lower day 100 response rates (very good partial response or better: 35% vs 84%, P < .001). After consolidation, rates of very good partial response improved from 24% to 28%, and rates of complete response improved from 11% to 40%. Patients with less than very good partial response who received consolidation, had better progression-free survival (median of 22.4 vs 8.8 months, P < .001), and the benefit was greater in those who deepened their response (median of 41 vs 8.8 months, P < .001). In patients with less than very good partial response, there was a trend for better overall survival in patients who responded to consolidation (median of 125.8 vs 74.4 months, P = .07). In patients who achieved very good partial response, or better, at day 100 post autologous stem cell transplant, consolidation did not improve progression-free or overall survival. Consolidation after autologous stem cell transplant for light chain amyloidosis improves progression-free survival for patients who achieve less than very good partial response.
Ibrutinib maintenance following induction for untreated mantle cell lymphoma (MCL): Initial safety report.
Authors: Reem Karmali, Jeremy S. Abramson, Deborah Marie Stephens, Jeffrey A. Barnes, Jason B. Kaplan, Jane N. Winter, Shuo Ma, Adam Matthew Petrich, Ephraim P. Hochberg, Tak Takvorian, Valerie Nelson, Leo I. Gordon, Barbara Pro
Journal: Journal of Clinical Oncology (2019)

7542 Background: Maintenance rituximab in MCL has improved survival, though the optimal approach is not yet defined. Ibrutinib, a selective BTK inhibitor, has profound activity in R/R MCL. Ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction. Methods: Patients with MCL with CR/PR to frontline chemo-immunotherapy (+/- autoSCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3 year PFS rate. Secondary objectives were PR to CR conversions, median OS at 4 years and toxicity with MRD assessments planned. Results: Accrual is complete with 36 patients, median age of 60 (range 46-90), 28 males, 28 with advanced stage and 9 with extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. 8/24 patients had a Ki-67 &gt; / = 30%. For induction, 17 (47%) received BR, 18 (50%) a cytarabine-based regimen, 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. At median follow-up of 19 mos, 24/36 (67%) patients remain on I-M (median 15 cycles, range 1-49) with 1 PD and 1 death. TRAEs led to dose reductions/interruptions in 25 (69%) patients, including permanent dose reductions in 7 (19%) and treatment discontinuation in 9 (25%; Table). 3 additional patients discontinued I-M, 1 for endometrial adenocarcinoma, 1 PD, 1 death, cause unknown. Conclusions: Ibrutinib maintenance is feasible in MCL patients who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with prior reports of ibrutinib. Additional follow-up and MRD status correlations with PFS and OS will provide insight on clinical relevance for this approach. Clinical trial information: NCT02242097. [Table: see text]
Continual hemodynamic monitoring with a single-use transesophageal echocardiography probe in critically ill patients with shock: a randomized controlled clinical trial
Authors: Tobias M. Merz, Luca Cioccari, Pascal M. Frey, Andreas Bloch, David Berger, Bjoern Zante, Stephan M. Jakob, Jukka Takala
Journal: Intensive Care Medicine (2019)
Abstract 4371: To investigate the role of heme flux and function in growth and progression of NSCLC <i>in vivo</i>
Authors: Adnin Ashrafi, Poorva Ghosh, Sagar Sohoni, Li Zhang
Journal: Cancer Research (2019)

Abstract Lung cancer is the leading cause of cancer-related mortality and about 85% of the cases are non-small cell lung cancer (NSCLC). Previous research from our lab has shown that the levels of rate limiting heme biosynthetic enzyme ALAS1, heme uptake proteins HCP1 and HRG1 and oxygen utilizing hemoproteins are strongly elevated in NSCLC cells. Furthermore, specific inhibition of heme synthesis using a well-known inhibitor suppresses NSCLC cell proliferation, colony formation and migration compared to normal cells. These results suggest that heme flux and function is important for NSCLC growth and progression. Lentiviral particles overexpressing eGFP, Alas1, HRG1, and HCP1 were used to transfect NSCLC cell lines. Tumorigenic properties of these cells were analyzed in vitro using invasion, migration and colony formation assay. These cell lines were used to implant subcutaneous xenografts in NOD/SCID mice (n=6). Tumor growth was monitored using Bioluminescence imaging (BLI) and Vernier caliper measurements over a period of five weeks. Mice were sacrificed, tumor tissues were harvested and processed and embedded into FFPE blocks. The tissue sections were then used for histopathological analysis (Hematoxylin and Eosin staining) and immunohistochemistry experiments. Our data show a significant increase in invasion, migration and colony formation properties of cells lines overexpressing Alas1, HRG1 and HCP1 compared to eGFP overexpressing cell lines (Control) in vitro. At week 5, BLI radiance (total photons/seconds), tumor volumes and masses of Alas1, HCP1 and HRG1 overexpression subcutaneous tumor xenografts were significantly higher compared to eGFP overexpression controls. This was further corroborated by H and E staining. Our results demonstrate that overexpression of heme synthesis and uptake proteins causes an increase in tumorigenic properties of NSCLC cells in vivo. Thus, heme flux and function plays an important role in growth and progression of NSCLC. Further studies are underway to discern the molecular mechanisms underlying the role of heme in lung tumor growth. Citation Format: Adnin Ashrafi, Poorva Ghosh, Sagar Sohoni, Li Zhang. To investigate the role of heme flux and function in growth and progression of NSCLC in vivo [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 4371.
Clinical value of event-free survival (EFS) in acute myeloid leukemia (AML).
Authors: Abhishek Maiti, Hagop M. Kantarjian, Vinita Popat, Carlos Blanco, Miguel Velasquez, Guillermo Garcia-Manero, Marina Konopleva, Srdan Verstovsek, Michael Andreeff, Gautam Borthakur, Tapan M. Kadia, Naval Guastad Daver, Naveen Pemmaraju, Courtney Denton Dinardo, Sherry A. Pierce, William G. Wierda, Steven Mitchell Kornblau, Farhad Ravandi, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2019)

e18513 Background: EFS is not considered a robust end-point for AML trials. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may be valuable due to patients (pts) staying in remission and thus decreasing health care utilization (HCU). Methods: In this retrospective study we identified AML pts treated on frontline therapy trials at our institute from 2003-2013 with EFS ≥2 months (mo) and OS of 12-36 mo. We captured the amount of HCU from diagnosis till death, including number of clinic and emergency room (ER) visits, hospitalizations, consultations, blood product transfusions, invasive procedures, laboratory and imaging studies. Linear regression and product-moment correlation were used to determine the relation between these parameters and EFS. Results: Among 337 pts meeting inclusion criteria, the median age was 65 years, 30% had adverse risk AML, 47% received intensive chemotherapy (IC) and 27% received hypomethylating agents (HMA). The median EFS was 10.8 mo. Increasing EFS led to statistically significant decline in HCU for all patients regardless of OS and the correlations were stronger for pts achieving a complete remission (CR, Table). These observations held true across European LeukemiaNet risk groups, younger and older pts, and those receiving IC, HMA, and non-IC, with or without other agents. Conclusions: In newly diagnosed AML, improvement in EFS is correlated with decrease in all HCU irrespective of OS duration. [Table: see text]
Abstract 3066: The expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 in breast cancer
Authors: Erina Iwabuchi, Yasuhiro Miki, Kiyoshi Takagi, Yoshiaki Onodera, Yukiko Shibahara, Takanori Ishida, Takashi Suzuki, Hironobu Sasano
Journal: Cancer Research (2019)

Abstract Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 is a protein reported to be involved in tumor cell proliferation in breast cancer. The presence of intratumoral CEACAM8 positive neutrophils has been reported as an independent prognostic factor in both renal cell and hepatocellular cancer. In addition, CEACAM6 and 8 form a heterodimer; however, the possible interactions of these two proteins remain unclear in breast cancer. Therefore, in this study we first immunolocalized CEACAM6 and 8 in surgical pathology specimens of breast cancer. We examined 109 breast cancer and 20 metastatic breast cancer patients in this study. We then established MCF-7 cells (CEACAM6 positive) stably transfected with CEACAM8 and analyzed the interaction between CEACAM6 and CEACAM8 using proximity ligation assay (PLA) and further evaluated cell proliferation, invasion, and adhesion. Results of immunohistochemical analysis revealed that the number of CEACAM6 positive breast cancer cells was significantly higher in patients with low histological grade and stage also in CEACAM8 positive cells. The number of CEACAM6 and 8 double positive breast cancer cells was significantly higher in patients with low stage. In addition, CEACAM6 and 8 interaction was detected using the PLA through high expression of both in MCF-7 cells. Furthermore, their co-expression promoted cell adhesion of MCF-7 cells to the monolayer of endothelial cells but suppressed both cell invasion and proliferation. In metastatic breast cancer, CEACAM6 status was significantly higher in bone metastases than in lung metastases. To the best of our knowledge, this is the first study demonstrating the expressions of CEACAM6 and 8 in breast cancer. Results of our present study also indicated that both CEACAM6 and CEACAM8 could be involved in less aggressive subtypes of breast cancer possibly trough inhibition of vascular invasion and proliferation. In addition, results indicated that CEACAM6 was involved in breast cancer metastases to the bone but further studies are required to clarify the clinical significance of their interactions in breast cancer patients. Citation Format: Erina Iwabuchi, Yasuhiro Miki, Kiyoshi Takagi, Yoshiaki Onodera, Yukiko Shibahara, Takanori Ishida, Takashi Suzuki, Hironobu Sasano. The expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 in breast cancer [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 3066.
Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model
Authors: Malick M. Gibani, Elizabeth Jones, Amber Barton, Celina Jin, Juliette Meek, Susana Camara, Ushma Galal, Eva Heinz, Yael Rosenberg-Hasson, Gerlinde Obermoser, Claire Jones, Danielle Campbell, Charlotte Black, Helena Thomaides-Brears, Christopher Darlow, Christina Dold, Laura Silva-Reyes, Luke Blackwell, Maria Lara-Tejero, Xuyao Jiao, Gabrielle Stack, Christoph J. Blohmke, Jennifer Hill, Brian Angus, Gordon Dougan, Jorge Galán, Andrew J. Pollard
Journal: Nature Medicine (2019)

Salmonella Typhi is a human host-restricted pathogen that is responsible for typhoid fever in approximately 10.9 million people annually1. The typhoid toxin is postulated to have a central role in disease pathogenesis, the establishment of chronic infection and human host restriction2–6. However, its precise role in typhoid disease in humans is not fully defined. We studied the role of typhoid toxin in acute infection using a randomized, double-blind S. Typhi human challenge model7. Forty healthy volunteers were randomized (1:1) to oral challenge with 104 colony-forming units of wild-type or an isogenic typhoid toxin deletion mutant (TN) of S. Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38 °C for ≥12 h and/or S. Typhi bacteremia) between participants challenged with wild-type or TN S. Typhi (15 out of 21 (71%) versus 15 out of 19 (79%); P = 0.58). The duration of bacteremia was significantly longer in participants challenged with the TN strain compared with wild-type (47.6 hours (28.9–97.0) versus 30.3(3.6–49.4); P ≤ 0.001). The clinical syndrome was otherwise indistinguishable between wild-type and TN groups. These data suggest that the typhoid toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human challenge model. Further clinical data are required to assess the role of typhoid toxin in severe disease or the establishment of bacterial carriage. Typhoid toxin is not essential for the pathogenesis of typhoid fever in healthy humans challenged with Salmonella Typhi.
Outbreak of human monkeypox in Nigeria in 2017–18: a clinical and epidemiological report
Authors: Adesola Yinka-Ogunleye, Olusola Aruna, Mahmood Dalhat, Dimie Ogoina, Andrea McCollum, Yahyah Disu, Ibrahim Mamadu, Afolabi Akinpelu, Adama Ahmad, Joel Burga, Adolphe Ndoreraho, Edouard Nkunzimana, Lamin Manneh, Amina Mohammed, Olawunmi Adeoye, Daniel Tom-Aba, Bernard Silenou, Oladipupo Ipadeola, Muhammad Saleh, Ayodele Adeyemo, Ifeoma Nwadiutor, Neni Aworabhi, Patience Uke, Doris John, Paul Wakama, Mary Reynolds, Matthew R Mauldin, Jeffrey Doty, Kimberly Wilkins, Joy Musa, Asheena Khalakdina, Adebayo Adedeji, Nwando Mba, Olubunmi Ojo, Gerard Krause, Chikwe Ihekweazu, Anna Mandra, Whitni Davidson, Victoria Olson, Yu Li, Kay Radford, Hui Zhao, Michael Townsend, Jillybeth Burgado, Panayampalli S. Satheshkumar
Journal: The Lancet Infectious Diseases (2019)
Abstract 1190: Tissue slice culture platform: A slice of reality in drug development
Authors: Shannon Burke, Fabien Garcon, Kelli Ryan, James Harper, Robert W. Wilkinson
Journal: Cancer Research (2019)

Abstract Immuno-oncology (IO) therapies for cancer have recently delivered step-change improvements in patient outcomes, but the major proportion of patients remain unresponsive or become refractory to IO treatment. Because IO-based approaches necessarily rely on the interplay of multiple cell types, including immune cells, and other elements that constitute the tumor microenvironment (TME), innovative assays are critical to generate further translational insight. Indeed, results from in vivo mouse models and in vitro assays with human cell lines often do not correlate with clinical efficacy and as such, do not always represent relevant avatars. We have leveraged recent advances in tumor slice culture (TSC) techniques to enable in vitro mechanistic and novel biomarker testing/identification studies. TSC involves the in vitro culture of thick slices (200-300 μm) of fresh tissue prepared using a vibratome and is currently the only in vitro assay system which retains the 3-dimensional tissue architecture, complete with cell-cell and cell-matrix interactions. We are now regularly using the TSC together with tumor samples derived from patients and human cancer cell line derived xenograft or syngeneic mouse cancer models, to generate exciting pre-clinical data for several Oncology programs, including oncolytic viruses, modified RNA, bispecific antibodies and antibody-drug conjugates. For instance, the TSC platform has allowed us to analyse the strong type I IFN-driven inflammatory response initiated by infection of tumor nests within patient samples and demonstrate the consequent infiltration of immune cells from the surrounding stroma. Thus, using a tissue phenomics approach incorporating a range of endpoint assays, including multiplex whole-mount imaging, transcriptomics and cytokine expression, the data generated using the TSC platform will inform the underlying biology and translational strategies of multiple therapeutic candidates. Citation Format: Shannon Burke, Fabien Garcon, Kelli Ryan, James Harper, Robert W. Wilkinson. Tissue slice culture platform: A slice of reality in drug development [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 1190.
Abstract 15163: Social Determinants of Cardiovascular Health in US Adolescents: National Health and Nutrition Examination Surveys (NHANES) 1999-2014
Authors: Sean D Connolly, Amanda Perak, Lindsay Pool, Hongyan Ning, Bradley Marino, Donald M Lloyd-Jones
Journal: Circulation (2018)

Introduction: Overall cardiovascular health (CVH) in US adolescents is poor. Associations between social determinants of health (SDH) and CVH in adolescents have not been described, yet SDH may pla...
Abstract 18268: Defining Left Atrial Mass: Correlation Between Anatomy and Echocardiogram
Authors: Purvi J Parwani, Phillip Ursell, Qizhi Fang, Neslon Schiller
Journal: Circulation (2017)

Introduction: Since Left atrial(LA) enlargement signifies increased risk of adverse cardiovascular consequences for the patient, a measure of LA volume is requisite for any complete transthoracic e...