tbuckley/cabot-search huggingface dataset:
T-cell large granular lymphocytic leukemia evolution post-transplant: The Cleveland Clinic experience.
Authors: Hassan Awada, Jibran Durrani, Fahrettin Covut, Bicky Thapa, Reda Z. Mahfouz, Cassandra M. Kerr, Yasunobu Nagata, Vera Adema, Betty Ky Hamilton, Valeria Visconte, Navneet S. Majhail, Mikkael A. Sekeres, Ronald M. Sobecks, Jaroslaw P. Maciejewski
Journal: Journal of Clinical Oncology (2019)

e19072 Background: T-cell large granular lymphocytic leukemia (LGLL) has been reported after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT); yet its underlying pathophysiological evolution has been poorly explained. Methods: We retrospectively screened a cohort of 243 LGLL patients at Cleveland Clinic for disease development post-transplantation and postulated several possible responsible pathophysiological mechanisms. Results: Five percent (n = 12) of the patients had a history of transplant. Of these, 67% (n = 8) had SOT (kidney, liver or heart) while 33% (n = 4) had HSCT. Twenty-five percent were females while 75% were males. The median age was 56 years (range: 15-65). The median time from transplant to diagnosis was 7 years. Conventional cytogenetic showed normal karyotype in 89% of the patients. TCR gene re-arrangement by PCR was detected in all tested individuals. Targeted deep sequencing identified somatic STAT3 mutations in 17% (n = 2) of the cases. Fifty percent (n = 6) had EBV DNA, IgM and/or IgG post-transplant. Forty-two percent (n = 5) had CMV DNA, IgM and/or IgG; of which 80% (n = 4) were post-transplant and 20% (n = 1) pre-transplant. The median survival from disease diagnosis was 64.3 months (8.37-232.9). Indeed, T-LGL clonal expansion resulted from long-term stimulation by viral antigens including EBV and CMV causing continuous cytotoxic T cell immune response or by “oncomodulation” as explained in 83% of patients. The latter theory suggests that CMV infects tumor cells and modulates their malignant properties, without direct transformation. Immunosuppression in setting of pre-transplant exposure to CMV, caused reactivation of the latent oncogenic viral genome as seen in 8% of patients. In 17% of cases that were seronegative for viral genome, graft allo-antigenic stimulation has triggered long-term recipient LGLL expansion from antigenic mismatch. Somatic STAT3 mutations, which are highly expressed in leukemic LGL, has led to aberrant signaling and transformation (17%). Conclusions: Our study highlights the complex nature of LGLL evolution post SOT and HSCT and points out confounding mechanisms. Certainly, investigating pre- vs. post-transplantation baseline, clinical and molecular characteristics is warranted to deeply understand this phenomenon.
Comparative Efficacy and Safety of Gemtuzumab Ozogamicin (GO) Plus Daunorubicin-Cytarabine Combination and Comparators As Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia
Authors: Ajibade Ashaye, Zarmina S. Khankhel, Yingxin Xu, Kyle Fahrbach, Ruth Mokgokong, Michelle Orme, Kathryn Lang, Joseph C. Cappelleri, Carla M. Mamolo
Journal: Blood (2017)
Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination
Authors: Yongzhen Liu, Hui Liu, Zhanying Hu, Yang Ding, Xiao‐Ben Pan, Jun Zou, Jingyuan Xi, Guangxin Yu, Hongxin Huang, Meng‐Ting Luo, Fang Guo, Shuang Liu, Qiuju Sheng, Jidong Jia, Yong‐Tang Zheng, Jie Wang, Xiangmei Chen, Ju‐Tao Guo, Lai Wei, Fengmin Lu
Journal: Hepatology (2019)

Nucleos(t)ide analogues (NAs) have been widely used for the treatment of chronic hepatitis B (CHB). Because viral DNA polymerase lacks proofreading function (3′ exonuclease activity), theoretically, the incorporated NAs would irreversibly terminate viral DNA synthesis. This study explored the natures of nascent hepatitis B virus (HBV) DNA and infectivity of progeny virions produced under NA treatment. HBV infectivity was determined by infection of HepG2‐NTCP cells and primary human hepatocytes (PHHs). Biochemical properties of HBV DNA in the progeny virions were investigated by qPCR, northern blotting, or Southern blotting hybridization, sucrose gradient centrifugation, and in vitro endogenous DNA polymerase assay. Progeny HBV virions produced under NA treatment were mainly not infectious to HepG2‐NTCP cells or PHHs. Biochemical analysis revealed that under NA treatment, HBV DNA in nucleaocapsids or virions were predominantly short minus‐strand DNA with irreversible termination. This finding was supported by the observation of first disappearance of relaxed circular DNA and then the proportional decline of HBV‐DNA levels corresponding to the regions of PreC/C, S, and X genes in serial sera of patients receiving NA treatment. Conclusion: HBV virions produced under NA treatment are predominantly replication deficient because the viral genomes are truncated and elongation of DNA chains is irreversibly terminated. Clinically, our results suggest that the viral loads of CHB patients under NA therapy vary with the different regions of genome being detected by qPCR assays. Our findings also imply that NA prevention of perinatal and sexual HBV transmission as well as infection of transplanted livers works not only by reducing viral loads, but also by producing noninfectious virions.
Abstract 3691: XPC inhibits lung cancer cell dedifferentiation by suppressing Snail expression
Authors: Shurui Cai, Dayong Wu, Ananya Banerjee, Lu Liu, Chunhua Han, Tiantian Cui, Qi-En Wang
Journal: Cancer Research (2019)

Abstract Lung cancer remains a leading cause of cancer-related deaths in the United States with unfavorable prognosis mainly due to tumor relapse and metastasis, which are recently believed to be caused by a specific population of cancer cells within tumor termed “cancer stem cells (CSCs)”. These cells share the common characteristic of self-renewal and differentiation as normal stem cell, but also show resistance to chemotherapy and radiation therapy. Thus, targeting CSC populations in lung tumors is critical to the prevention of tumor metastasis. Xeroderma pigmentosum group C (XPC) was first recognized as a DNA repair protein. As a DNA repair factor, XPC plays an important role in preventing carcinogenesis. However, it has also been reported that XPC insufficiency is associated with poor treatment outcomes for a variety of cancers, and low expression of XPC is correlated with poor prognosis of lung cancer patients, suggesting that XPC may suppress lung cancer progression. Here, we show that downregulation of XPC expanded lung CSCs characterized by CD133+, while overexpression of XPC limited this cell population, as well as reduced the tumorigenic potential of the lung cancer cell line. Furthermore, we found that XPC knockdown is able to promote the CD133--to-CD133+ cell conversion in A549 cells, indicating that XPC can inhibit lung cancer cell dedifferentiation. Mechanistic investigation demonstrated that XPC can suppress Snail expression by directly binding to the promoter region of the SNAI1 gene, leading to the enrichment of histone H3 trimethylation at serine 27 (H3K27me3) and loss of histone H3 acetylation at serine 27 (H3K27Ac) in this region. Given that Snail plays a critical role in the induction of epithelial-mesenchymal transition (EMT), which is a major mechanism for the acquisition of stem cell-like properties, we believe that XPC can limit the CSC population by inhibiting cancer cell dedifferentiation. In summary, we conclude that low expression of XPC in lung tumors can de-repress the expression of Snail, promote EMT, and increase the de novo production of CSCs, eventually facilitating lung tumor progression. Citation Format: Shurui Cai, Dayong Wu, Ananya Banerjee, Lu Liu, Chunhua Han, Tiantian Cui, Qi-En Wang. XPC inhibits lung cancer cell dedifferentiation by suppressing Snail expression [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 3691.
Outcomes of treatment for non-metastatic rectal cancer; a ten year single institute experience at the Bank of Cyprus Oncology Centre (BOCOC)
Authors: I. Konstantinou, E. Xenophontos, P. Papanastasopoulos, V. Vassiliou, P. Kountourakis, P. Vogazianos, D. Papamichael
Journal: Annals of Oncology (2019)
Abstract 16871: Improving the Diagnosis of Culprit Left Circumflex Occlusion With Acute Myocardial Infarction in Patients With a Non-diagnostic 12-lead ECG at Presentation: A Retrospective Cohort Study
Authors: Michael J Daly, Peter J Scott, Mark T Harbinson, Jennifer A Adgey
Journal: Circulation (2017)

Introduction: Patients with acute left circumflex artery (LCx) occlusion may present with inferior or lateral ST-elevation myocardial infarction (STEMI) or non-STEMI on 12-lead ECG. Non-STEMI patie...
Abstract 3136: Discovery of low abundance colorectal cancer related biomarkers by the ADAPT Biotargeting System
Authors: Tassilo Hornung, Jelena Zarkovic, Michelle Kassner, Matthew Rosenow, Mark R. Miglarese, Günter Mayer, Michael Famulok, David B. Spetzler
Journal: Cancer Research (2019)

Abstract Disease biomarkers play an essential role in disease-diagnostics and in monitoring their responses to therapies. Identification of low to medium abundance biomarkers is one of the biggest challenges in the field. We have developed Adaptive Dynamic Artificial Poly-ligand Targeting (ADAPT), a method in which libraries of single-stranded oligodeoxynucleotides (ssODNs) are enriched for sequences that bind to targets existing in samples in various amounts. Pull-downs with enriched libraries followed by LC-MS/MS allows for the enrichment and identification of low abundance biomarkers that cannot be identified by conventional proteomics. A highly diverse library of 1011 ssODNs was subjected to multiple rounds of positive selection against formalin-fixed paraffin-embedded (FFPE) colorectal cancer tissue with negative selection against adjacent non-cancer tissue of the same specimen. An enriched library of ~3x106 ssODNs that bound preferentially to cancer tissue was obtained and used in combination with LC-MS/MS to identify biomarkers related to colorectal cancer. Using this approach, a total of 14 proteins were identified in cancer but not in non-cancer tissue lysates. Their identification was only possible due to their enrichment by binding of the immobilized ssODN library to the cancer sample since the same proteins were undetectable by conventional proteomics. Immunohistochemical staining (IHC) of multiple colorectal cancer cases verified that several of the identified target proteins, including nucleophosmin (NPM1) and synaptotagmin-like protein 2 (SYTL2), showed higher expression in cancer tissue compared to adjacent non-cancer tissue. Our data indicate the potential of the ADAPT platform to profile small differences between cancer affected and unaffected tissue and provide a novel approach for cancer biomarker discovery. Citation Format: Tassilo Hornung, Jelena Zarkovic, Michelle Kassner, Matthew Rosenow, Mark R. Miglarese, Günter Mayer, Michael Famulok, David B. Spetzler. Discovery of low abundance colorectal cancer related biomarkers by the ADAPT Biotargeting System [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 3136.
Abstract 15674: Walking Impairment Questionnaire Adds Predictive Value for Adverse Cardiac and Limb Events in Patients With Peripheral Arterial Disease
Authors: Rebecca M LeLeiko, Robert T Eberhardt, Monika Holbrook, Joseph N Palmisano, Na Wang, Farhana Sharmeen, Abhishek Khemka, Alik Farber, Ashvin N Pande, Noyan Gokce, Joseph A Vita, Naomi M Hamburg
Journal: Circulation (2013)

Background: Peripheral arterial disease (PAD) is associated with a high risk of adverse cardiac and limb events. Functional disability confers increased risk of mortality in PAD. Whether functional...
Abstract 1142: An activity-dependent proximity ligation platform for spatially resolved and multiplexed quantifications of active enzymes in single cells
Authors: Gang Li, Raymond E. Moellering
Journal: Cancer Research (2019)

Abstract Integration of chemical probes into proteomic workflows enables the interrogation of protein activity, rather than abundance. Current methods limit the biological contexts that can be addressed due to sample homogenization, signal-averaging, and bias toward abundant proteins. To expand the application scope of chemical proteomics and explore the cellular heterogeneity on enzyme activities, we developed a new platform that integrates family-wide chemical probes with proximity-dependent oligonucleotide amplification and imaging to quantify enzyme activity in native contexts with high spatial and single cell resolution. Application of this method, activity-dependent proximity ligation (ADPL), to serine hydrolase and cysteine protease enzymes enables quantification of differential enzyme activity resulting from endogenous changes in localization and expression. In a competitive format, small molecule target engagement with endogenous proteins in live cells can be quantified. Retention of sample architecture enables interrogation of complex environments such as cellular co-culture and patient samples. We also successfully applied ADPL in xenograft tissue sample, exhibiting the application prospect in primary patient tissue. Additionally, implementation of barcoded antibody-oligo direct conjugation enabled multiplexed readout of active enzymes within and between enzyme families, providing the possibility of simultaneous biomarker detection. Together, this work supports ADPL should be amenable to diverse and multiplexed protein families to detect active enzymes at scale and resolution out of reach with current methods. Citation Format: Gang Li, Raymond E. Moellering. An activity-dependent proximity ligation platform for spatially resolved and multiplexed quantifications of active enzymes in single cells [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 1142.
Abstract 1525: Kaiso influences immune signaling of breast cancer exosomes
Authors: Md Shakir U. Ahmed, Brittany Jenkins, Benjamin Adu-Addai, Balasubramanyam Karanam, Melissa B. Davis, William E. Grizzle, Honghe Wang, Clayton C. Yates
Journal: Cancer Research (2019)

Abstract Introduction: Exosomes are communication vesicles between tumor cells and immune cells. However, the mechanism underlining this cell-cell communication is not well understanding, particularly in African American (AA) breast cancer patients. Kaiso, a bi-modal transcription factor is highly expressed in AA patients and high Kaiso expression correlates with aggressiveness and the disparity in survival outcomes compared to European American (EA) patients. However, the biological consequences of Kaiso in immune signaling of breast cancer exosomes has not been studied. Herein we demonstrate the biological role of Kaiso in immune signaling in breast cancer exosomes. Methods: We utilized Nanostring immune profiling technology along with multiple in vitro and in vivo assays to study the role of Kaiso in breast cancer immune escape. Results: Nanostring pan cancer immune profiling showed that EA breast cancer exosomes exhibited higher expression of TILs markers, T cell activation markers and CD8+T Cells markers compared to AA, while we observed an increase in the expression of anti-phagocytic molecule CD47 in breast cancer patient exosomes of AA compared to EA. In addition to that CD47 and SIRP-α (Signal Regulatory Protein) are highly expressed in Kaiso-scrambled MDA-MB-231 cells (sh-SCR) and exosomes, whereas THBS1, which is a regulator of CD47 expression and is regarded as angiogenesis inhibitor is significantly increased in sh-Kaiso MDA-231 cells and exosomes. Additionally, we observed that Kaiso directly binds methylated sequences in the promoter region of CD47 and THBS1 by ChIP assay. Furthermore, in vivo sh-Kaiso cells injected into athymic mice exhibited delayed tumor formation after four weeks with smaller tumor size as compared to sh-SCR cells, and we observed higher expression of THBS1 with lower expression of CD47 and SIRP-α molecules by IHC and exosomes isolated from invivo tumors, indicating that Kaiso is associated with macrophage mediated immune escape. Conclusion: Our findings demonstrate the role of kaiso in immune signaling through exosomes which may be related with more aggressive cancer phenotype in breast cancer specially in African Americans. Citation Format: Md Shakir U. Ahmed, Brittany Jenkins, Benjamin Adu-Addai, Balasubramanyam Karanam, Melissa B. Davis, William E. Grizzle, Honghe Wang, Clayton C. Yates. Kaiso influences immune signaling of breast cancer exosomes [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 1525.
Electroencephalography-Guided Anesthetic Administration and Postoperative Delirium
Authors: Peter Kienbaum, Maximilian S. Schaefer
Journal: JAMA (2019)

To the Editor In a well-designed trial,1 EEG-guided anesthetic administration did not decrease the incidence of postoperative delirium. The authors concluded that their findings do not support the use of EEG-guided anesthesia for this indication.
Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: A systematic review and meta-analysis.
Authors: Stefano Molica, Diana Giannarelli, Emili Montserrat
Journal: Journal of Clinical Oncology (2019)

e19003 Background: Chronic lymphocytic leukemia (CLL) patients with undetectable minimal residual disease (U-MRD) (i.e., &lt; 10 -4 ) after upfront chemotherapy (CT) or chemo-immunotherapy (CIT) have better outcomes than those with detectable MRD (D-MRD). To validate the importance of achieving U-MRD and to assess the magnitude of improvement in progression free survival (PFS) and overall survival (OS) we conducted a systematic review and meta-analysis. Methods: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. Results: Eleven studies comprising 2457 CLL patients treated upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Four studies (n = 924) analyzed the impact of U-MRD on both PFS and OS while 8 studies (n = 1984) provided data only on PFS and 6 (n = 1074) exclusively on OS. U-MRD status was associated with significantly longer PFS overall (P &lt; .001) and in patients who achieved complete remission (CR) according to the International Workshop on CLL (IWCLL) guidelines (P = 0.01). Tests of heterogeneity revealed significant differences across studies evaluating PFS in both patients with U-MRD (Q = 49.27; P = 0.00; I 2 = 80%) and D-MRD (Q = 199.15; P = 0.00; I 2 = 95%). OS was also longer in patients with U-MRD overall (P &lt; .001). Test of heterogeneity revealed no significant differences across studies evaluating OS in patients with U-MRD (Q = 9.16; P = 0.06; I 2 = 56%). Of note, U-MRD did not predict for a longer OS in patients who achieved IWCLL CR. (P = 0.82). This contrasts with data from single series and needs prospective assessment. Conclusions: This study validates the importance of achieving U-MRD in newly diagnosed patients with CLL treated with CT or CIT and provides quantitative evidence of the improvement regarding PFS and OS. MRD status should be incorporated as endpoint into prospective clinical trials and in the evaluation of new agents for CLL therapy as already accepted by the European Medicines Agency (EMA). The clinical significance of MRD in patients treated with BCR or BCL2 inhibitors is largely unknown and warrants study.
Regionalization of Care and the Maternal-Infant Dyad Disconnect
Authors: Sara C. Handley, Sindhu K. Srinivas, Scott A. Lorch
Journal: JAMA (2019)

This Viewpoint argues for thinking about improvements in the care of new moms and infants as a single entity, and discusses regionalization of obstetric and infant care as a way to operationalize the idea and achieve simultaneous improvements in maternal and neonatal outcomes.
Chemotherapy rechallenge or reintroduction, regorafenib, and TAS-102 for metastatic pretreated colorectal cancer patients: a propensity score analysis of treatment beyond the second line (PROSERpINA Study)
Authors: M. Calegari, I. Zurlo, M. Basso, A. Orlandi, M. Bensi, F. Camarda, B. Di Stefano, R. Vivolo, C. Pozzo, I. Sperduti, E. Bria, L. Salvatore, G. Tortora
Journal: Annals of Oncology (2019)
Abstract 15550: Impact of PET Imaging to Visualize Activated Macrophages in Immune Rejection of Allogenic iPS Derived Cardiac Myocytes in Mice
Authors: Noriyuki Kashiyama, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Shigeo Masuda, Takuji Kawamura, Ai Kawamura, Shohei Yoshida, Akima Harada, Takayoshi Ueno, Koichi Toda, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2015)

Introduction: Transplantation of allogeneic cells inevitably induce activated macrophage-related host immune response, which would limit therapeutic effects. Importantly, monitoring magnitude of the immune response is poorly established in the allogeneic cell transplantation therapy for the heart. Hypothesis: In this study, we hypothesized that [18F]-DPA-714-PET imaging may visualize activated macrophages accumulated to the host heart after transplantation of allogeneic induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM). Methods: iPSC-CM cell-sheets of C57BL/6 mice origin were generated by the thermoresponsive dish and transplanted over the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (Group sTx), or Balb/c mice as an allogeneic one (Group aTx). The mice were examined by [18F]-DPA-714-PET to assess maximum standardized uptake value (SUVmax) ratio (A/S ratio) calculated by SUVmax in the anterior and septal wall of the LV. In addition, expression of factors associated with immune rejection was assessed by RT-PCR and the significance of immune rejection was evaluated by Immunochemical staining of CD3 or CD68 positive cell. Results: A/S ratio was comparable in all groups at 1 day (aTx: 1.19±0.05, sTx: 1.16±0.03, sham: 1.20±0.03, p=0.34), though higher in the aTx group than the other groups at 7 day (aTx: 1.38±0.03, p&lt;0.01, sTx: 1.18±0.04, sham: 1.25±0.09) after the cell transplantation. In addition, the expression of IL-2 and MCP-1 of the heart tissue were higher in the aTx group than the other groups at 7 day (aTx: 31.4±3.8, p&lt;0.01, sTx: 1.5±1.2, sham: 2.3±0.9 and aTx: 30.8±12.7, p&lt;0.01, sTx: 4.0±3.4, sham: 5.5±2.0). Furthermore, in the immunochemical histology, the percentages of CD3 and CD68 positive cells were also higher in the aTx group than the other groups at 7day. Conclusions: Accumulation of activated macrophages were identified in the LV surface more intensely after the allogeneic iPSC-CM transplantation than the syngeneic or sham one by the [18F]-DPA-714-PET imaging, warranting that PET imaging may be applicable in clinical setting of the allogeneic cell transplantation therapy to monitor magnitude of host immune response.