tbuckley/cabot-search huggingface dataset:
Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction
Authors: Domenico Girelli, Simonetta Friso, Elisabetta Trabetti, Oliviero Olivieri, Carla Russo, Renzo Pessotto, Giovanni Faccini, Pier Franco Pignatti, Alessandro Mazzucco, Roberto Corrocher
Journal: Blood (1998)
Pre-Transplant Hypomethylating Agents Do Not Influence Post-Transplant Outcomes in Myelodysplastic Syndrome
Authors: Dipenkumar Modi, Seongho Kim, Vijendra Singh, Asif Alavi, Lois Ayash, Voravit Ratanatharathorn, Joseph P. Uberti, Abhinav Deol
Journal: Blood (2018)
Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A)
Authors: Zhonghua Li, Lina Ding, Zhongrui Li, Zhizheng Wang, Fengzhi Suo, Dandan Shen, Taoqian Zhao, Xudong Sun, Junwei Wang, Ying Liu, Liying Ma, Bing Zhao, Pengfei Geng, Bin Yu, Yichao Zheng, Hongmin Liu
Journal: Acta Pharmaceutica Sinica B (2019)

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and Ki = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u. Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.
The eHealth service CANKADO to overcome nonadherence during oral self-medication.
Authors: Julian Kates-Harbeck, Rachel Wuerstlein, Ronald E. Kates, Nadia Harbeck, Timo Schinkothe
Journal: Journal of Clinical Oncology (2014)

e17520 Background: 25% of cancer drugs currently under development are intended for oral self-medication. This reflects the cancer patients' preferences, 54% - 89% of whom --- depending on the demographic subgroup --- prefer oral medication. However, the change from intravenous administration to oral self-medication leads to a loss of control of the physician in charge while the patient’s individual responsibility increases dramatically. A lack of therapy adherence is the main induced issue. Depending on the type of tumor and the therapy, up to 84% of all patients are not adequately adherent. Methods: CANKADO has been designed to support cancer patients during oral self-medication. It is intended to increase communication between stakeholders via a multi-channel communication concept and by incorporating findings of cognitive behavioral therapy. Results: CANKADO’s approach focuses on mitigating those reasons for non-adherence that are related to the patient or the therapy itself. Adherence is supported via a gamification strategy that incorporates both playful elements as well as conventional techniques from cognitive behavioral therapy. The goal is to increase adherence to an acceptable level with this combined approach. CANKADO provides patient care by means of a combined system of computer application and therapists where the physician in charge takes on the role of the therapist. The system expands the range of care services of the physician and provides the opportunity for interaction outside of personal meetings. Moreover, it offers tailored support measures to patients, physicians, and their assistants, respectively, via differentiated roles within the CANKADO framework. Conclusions: In summary, CANKADO provides a novel, eHealth-driven approach to overcome non-adherence. CANKADO is a non-profit service.
Comparison of false-negative probabilities for digital and film mammography within a large health care organization.
Authors: Firas M Dabbous, Jenna Khan-Gates, Terry Macarol, Therese A. Dolecek, Sally Friedewald, Anne Marie Murphy, Tom Summerfelt, Garth Rauscher
Journal: Journal of Clinical Oncology (2014)

1611 Background: Screening mammography as an early detection tool is susceptible to both false positive and false negative results. We compared false negative probabilities (FNP) for Full Field Digital Mammogram (FFDM) and Screen Film Mammography (SFM) in a single large healthcare organization. Methods: Screening mammograms between 2001 and 2009 were linked to incident breast cancer cases for the period 2001-2010 from the Illinois State Cancer Registry using probabilistic linkage methods. The linkage rate in a validation subsample of known breast cancers was 99%. A false negative mammogram (“interval cancer”) was defined as a normal finding by the original interpreting radiologist in a woman diagnosed with breast cancer in the subsequent 12 months. Results: There were 669,222 screens and 4,058 breast cancer cases (3,071 screen-detected, 988 interval cancers). As expected, overall FNP decreased with increasing age and increased with increasing breast density. Contrary to expectation, FNP was higher for FFDM vs. SFM (27% vs. 23%, p=0.01), though marginally lower for FFDM vs. SFM among women under age 50 (24% vs. 27%, p=0.28). FFDM was not associated with improved FNR for women with denser breasts or for tumor characteristics suggesting more aggressive disease (hormone receptor negative and higher grade). Conclusions: Our results run counter to other studies that have foundFFDM to be more accurate than SFM generally and specifically among women with dense breasts. Differences between studies may be in part a reflection of the community based nature of this sample of women and practicing radiologists.
Analysis of small cell lung cancer (SCLC) patients (Pts) treated on cancer therapy evaluation program (CTEP)-sponsored phase I trials: 1992-2012.
Authors: Patrick M. Forde, Craig M. Hooker, Larry Rubinstein, Christine L. Hann, Pamela Jo Harris
Journal: Journal of Clinical Oncology (2014)

7524 Background: Platinum-refractory SCLC has a poor prognosis with a median survival of 2-6 months. Second-line and later treatment options are limited and pretreated patients with preserved ECOG performance status (PS) are often considered for early phase clinical trials in solid tumors. We conducted an analysis of the CTEP database and report the largest cohort to date of SCLC pts treated on phase I studies. Methods: Data from all SCLC patients enrolled on CTEP-sponsored phase I trials from 1992-2012 were analyzed. Trials were conducted at the National Institutes of Health and other institutions in the United States under CTEP sponsorship. Trials were categorized as chemotherapy (C), biologic therapy (B), combined biologic-chemotherapy therapy (BC) or immunotherapy (I). Demographics, rates of toxicities, response rate (RR), clinical benefit rate (CBR = RR +stable disease rate) and treatment duration were analyzed using descriptive statistics. Results: 84 pts enrolled during the specified time period, (median age 59 (interquartile range, IQR 52 – 63) ECOG PS 0-1 86.9%; 2, 11.9%; 3, 1.2%). The cohort was heavily pretreated (median 4 lines (IQR 2 – 5)). Pts received the following treatment types (no. of pts (%)) - C, 47 (56%); B, 18 (21.4%); BC, 14 (16.7%); I, 5 (6%). Treatment-related toxicities occurred as follows – grade 1/2, 71 (84.5%); grade 3/4, 39 (46.4%); grade 5, 1 (1.9%). RR was 6 (7.1%) and the CBR was 23 (27.1%). Responses only occurred with C (4 pts) and BC (2 pts). Median treatment duration was 42 days (IQR 25 – 63). Conclusions: Toxicities in phase I SCLC pts are higher than those previously reported in the general population of phase I solid tumor pts (G3/4 toxicity rate 46.4% vs. 36-38% (CTEP & non-CTEP databases)). This may partly reflect a relatively higher proportion of SCLC pts with ECOG PS >1 (13.1% vs. 6% of unselected solid tumor pts on CTEP phase I studies). CBR and median treatment duration are comparable to SCLC pts who have been treated with single agent chemotherapy in the second or subsequent line setting but lower than those observed in the general phase I pt population. Phase I study enrollment represents a reasonable option for pretreated SCLC pts with good ECOG PS.
The Development of the ICD-11 Classification of Personality Disorders: An Amalgam of Science, Pragmatism, and Politics
Authors: Peter Tyrer, Roger Mulder, Youl-Ri Kim, Mike J. Crawford
Journal: Annual Review of Clinical Psychology (2019)

The nomenclature of personality disorders in the 11th revision of the International Classification of Diseases and Related Health Problems represents the most radical change in the classification history of personality disorders. A dimensional structure now replaces categorical description. It was argued by the Working Group that only a dimensional system was consistent with the empirical evidence and, in the spirit of clinical utility, the new system is based on two steps. The first step is to assign one of five levels of severity, and the second step is to assign up to five prominent domain traits. There was resistance to this structure from those who feel that categorical diagnosis, particularly of borderline personality disorder, should be retained. After lengthy discussion, described in detail here, there is now an option for a borderline pattern descriptor to be selected as a diagnostic option after severity has been determined.
Crizotinib in advanced ALK-positive non-small cell lung cancer: Results of a retrospective cohort in Complejo Hospitalario de Navarra, Spain.
Authors: Berta Hernandez, Maite Martinez, Lucia Teijeira, David Guerrero, Elena Mata, Irene Gil, Ainhoa Castillo, Juan Verdun, Jose Antonio Rivadeneira, Patricia Ochoa, Esther Aznarez, Idoia Morilla, Susana De La Cruz, Irene Hernandez, Maria Jose Lecumberri, Antonio Viudez, Ruth Vera
Journal: Journal of Clinical Oncology (2014)

e19158 Background: Crizotinib is an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and has been approved in several countries for treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). Methods: Between June 2010 and Dec 2013, 163 patients (pts) with NSCLC were ALK screened. ALK was detected by ALK break-apart FISH assay in 10 pts. We analyzedthe data of these 10 pts ALK+, who received or who are receiving crizotinib 250 mg BID. Results: Baseline characteristics: 10/163 pts were ALK + (6.1%). 7/10 females. Mean age: 56 years [35-78]. Histology: 9/10adenocarcinoma; 1/10 squamous. 4 never smokers; 5 former smokers; 1current smoker. All pts had EGFR wild-type status. 6/10 pts received ≥3 previous lines of therapy. All pts presented good response to previous pemetrexed administration. After 2 months of treatment, 8/10 pts obtained a clinical benefit with improvement in previous symptoms. 7 pts were assessable for response with 5 PR; 1 SD and 1 PD. Median duration of treatment for all pts (not mature) was 6.7 months (range 1 month- 19 months). Six pts are still in treatment. The most common adverse events included: vision disorder (70%), constipation (40%), elevated liver aminotransferase levels (20%), nausea (30%) and peripheral edema (30%). Two pts required a dose reduction due to a grade 3 hepatotoxicity. Conclusions: Clinical features, efficacyand side effect profile observed in our group are comparable to those reported in other studies.
Clinical outcomes and prognostic factors of patients with advanced non-small cell lung treated in clinical trials in Brazil: A single institution experience.
Authors: Ricardo Zylberberg, Tomas Reinert, David Paul Carbone, Luiz H. Araujo
Journal: Journal of Clinical Oncology (2014)

e19144 Background: Non-small cell lung cancer (NSCLC) is a leading cause of death in Brazil, and most cases are diagnosed in advanced stages. Whereas significant therapeutic progress has been achie...
Thoracic malignancies after Hodgkin lymphoma.
Authors: Elena Almagro, David Perez, Fernando Franco, Judit Rubio, Magda Palka, Miriam Mendez, Constanza Maximiano, Pablo Tutor, Susana Mellor, Mariano Provencio
Journal: Journal of Clinical Oncology (2014)

e19520 Background: Many patients with Hodgkin´s Lymphoma (HL) are cured but they have an increased risk of developing second neoplasms (SN). We analyzed and compared their long-term risk of developing thoracic malignancies (TM), (lung cancer or mesothelioma) to other neoplasms. Methods: We retrospectively analyzed from January 1968 to December 2012 a total of 514 patients with HL treated and monitored in our hospital. We reviewed as variables: date, age and initial staging at diagnosis, type of treatment (chemo, radiotherapy or combined), presence of bulky mass, date of SN diagnosis, type and staging of tumor (we included non- HL, leukemia, breast, colon, thyroid cancer, sarcoma and others) and overall survival (OS). The contrasts between proportions were performed using Chi-square test and the survival curves using the Kaplan-Meier method and logrank test. Results: SN occurred in 79 cases (16%) out of 514 patients.24 patients (30.4%) developed TM, 23 lung cancer, 1 mesothelioma and 55 (69.6%) other type of tumor. No differences were found between the average age at diagnosis of HL in both groups, 35.7 and 33.5 years respectively (p=0.56). The median elapsed time to the diagnosis of SN was 16.4 years in TM and 9.7 in others (p=0.03). In the group of patients with TM, 21 of 24 (88%) patients were men (p=0.001) whereas in the other tumors group no gender differences were found. 35 patients (44%) presented advanced stage (III or IV) at diagnosis of HL, 7 (20%) with TM and 28 (80%) with other tumors (p=0.074). 17 (70.8%) of patients with TM were smokers. Radiotherapy treatment was associated with increased risk of TM compared to other neoplasms (0R=2,9, IC95% 1.1-7.7 P=0.033). The OS from diagnosis of SN in TM and other tumors was 58% and 61% in the first year, and 28% and 42% in the fifth (p=0.54). The monitoring time median is 1 year in TM and 1.5 in others. Conclusions: Lung cancer and mesothelioma after Hodgkin’s lymphoma are much more prevalent in male patients. Radiotherapy in HL leads to raised risk of Thoracic Malignancies.Differences were found in the elapsed time to diagnosis of SN between TM and other tumors group, but we did not find any difference in overall survival between both groups.
Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
Authors: Hoibin Jeong, Sehui Kim, Beom-Ju Hong, Chan-Ju Lee, Young-Eun Kim, Seoyeon Bok, Jung-Min Oh, Seung-Hee Gwak, Min Young Yoo, Min Sun Lee, Seock-Jin Chung, Joan Defrêne, Philippe Tessier, Martin Pelletier, Hyeongrin Jeon, Tae-Young Roh, Bumju Kim, Ki Hean Kim, Ji Hyeon Ju, Sungjee Kim, Yoon-Jin Lee, Dong-Wan Kim, Il Han Kim, Hak Jae Kim, Jong-Wan Park, Yun-Sang Lee, Jae Sung Lee, Gi Jeong Cheon, Irving L. Weissman, Doo Hyun Chung, Yoon Kyung Jeon, G-One Ahn
Journal: Cancer Research (2019)

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. SIGNIFICANCE: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
Correlations between Pre-Transplant Treatment and Bone Marrow Response with Post-Transplant Outcomes in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation
Authors: Pinkal Desai, Alfadel Alshaibani, Xian Wu, Sangmin Lee, Jingmei Hsu, Ellen K. Ritchie, Michael Samuel, Sebastian A. Mayer, Adrienne A. Phillips, Usama Gergis, Tsiporah B. Shore, Koen Van Besien, Gail J. Roboz
Journal: Blood (2018)
Can alfa-fetoprotein response to sorafenib predict for response and overall survival in hepatocellular carcinoma?
Authors: Humdum Pasha Durrani, Hemant S. Murthy, Sirish Sanaka, Punam Punja, Salini Sathya Naidu, Prashanti Atluri
Journal: Journal of Clinical Oncology (2014)

e15127 Background: Alpha-fetoprotein(AFP) has been a marker for screening and early diagnosis of Hepatocellular carcinoma (HCC) for many years. It has been shown to potentially play a prognostic role in Hepatitis B Virus related HCC and as well as a marker of response after TACE for HCC. What is unknown is whether trends in AFP levels can be used to predict for response and survival in patients (pts) treated with sorafenib. Methods: We performed a retrospective chart review of pts using ICD9 codes in our electronic medical records. Pts with unresectable disease and initiated on treatment with sorafenib were included. Those who expired prior to the 3 month mark were excluded. We collected and analyzed data including - time to death from initiation of sorafenib and serum AFP values at diagnosis, before initiating sorafenib, at 3 mos. and at 6 mos. We separated pts who had a decline in AFP at 3 months of more than or less than a 20% and 50% at starting sorafenib. Results: 21 pts met the criteria for the study of the 56 charts reviewed. 13 had a <20% drop in AFP and 8 had a >20% drop in AFP. All pts, 8 (100%), who had >20% drop in AFP within 3 months of starting sorafenib were alive at time of review compared to 5(38%) of the <20% drop group (p=0.0058). Median survival for those pts with < 20% drop was 215 days, median survival of pts with < 50% drop in AFP at 3 months was 306 days; survival data for the responders could not be calculated since all of them are alive. Conclusions: Our data suggest that after starting sorafenib, a > 20% drop in AFP at 3 months can indicate better survival and response to sorafenib. Those pts who have a < 20% decline do worse. Early on, when it can make a difference, alternative therapies could be considered in those pts who have less than optimal decline in AFP. Prospective randomized studies are needed to validate these findings.
A tool to predict post-transcriptional instability related to the dysregulation of the SETD2 histone methyltransferase in renal cell carcinoma (RCC).
Authors: Mia D. Champion, Huihuang Yan, Jared Evans, Jeff Nie, Jeong-Heon Lee, Jaime I. Davila, Raymond Moore, Tamas Ordog, Zhiguo Zhang, Richard Wayne Joseph, A. Keith Stewart, Jean-Pierre A. Kocher, Eric Jonasch, Thai Huu Ho
Journal: Journal of Clinical Oncology (2014)

11072 Background: Recent studies report that dysregulation of the SETD2 histone methyltransferase in (RCC) decreases global histone 3 lysine 36 trimethylation (H3K36me3), resulting in mis-regulation of alternative splicing of associated exons. It remains unclear how disruptions of chromatin-based modifications contribute to tumorigenesis and can be leveraged to develop more potent treatment strategies. Methods: We performed ChIP-, RNA-, and exome- sequencing on matched human RCCs (SETD2 wt /mutant), and RCC cell lines. These datasets were used to develop a tool, ChIP-RNA-seqPRO, to identify regions of dysregulated epigenomic modifications and altered transcript splicing present in the tumor, but absent in a normal sample. The tool provides annotations relevant to post-transcriptional processing and known disease associations (e.g. cancer-associated RNA editing sites). In addition, ChIP-RNA-seqPRO calculates a Modification Association Score (MAS) from changes in ChIP-seq peak distribution, transcript splicing, and associated sequence repeats and variations in order to predict post-transcriptional instability that is correlated with the clinically aggressive tumor phenotype and identify novel therapeutic targets. Results: In addition to identifying novel, tumor-unique predicted transcript isoforms and regions of chromatin modification alteration, we have also identified tumor-unique RNA variations shared between samples. Greater than 40% of these sites are known RNA editing sites also identified in other cancers. In addition, gene lists with applied MAScores were analyzed for pathway enrichment. Pathways associated with predicted post-transcriptional instability in SETD2-deficient RCC included regulation of Hypoxia-Inducible Factor (HIF), MAPkinase associated signaling pathways, and the p73 transcription factor network (p-value < 0.05). Conclusions: Our findings demonstrate the utility of our methods in profiling the regulatory association between epigenomic modification and post-transcriptional processing, and offer unprecedented insight into how the instability of these processes drives the progression of RCC.
Genetic variations in innate immunity genes affect response to Coxiella burnetii and are associated with susceptibility to chronic Q fever
Authors: A.F.M. Jansen, T. Schoffelen, C.P. Bleeker-Rovers, P.C. Wever, M. Jaeger, M. Oosting, A. Adriaans, L.A.B. Joosten, M.G. Netea, M. van Deuren, E. van de Vosse
Journal: Clinical Microbiology and Infection (2019)
IMPROVE: mortality in psoriasis and psoriatic arthritis
Authors: L. Skov, S.F. Thomsen, L.E. Kristensen, R. Dodge, M.S. Hedegaard, J. Kjellberg
Journal: British Journal of Dermatology (2019)

This study from Copenhagen, Denmark set out to estimate whether there was an increased risk of death in patients with psoriasis. This common skin condition has been linked with a number of other illnesses such as heart disease which may affect a patient's life expectancy. In Denmark there is a National Patient Registry, which was used to compare death rates in patients with different clinical forms of psoriasis, including psoriatic arthritis, with a control group who did not have psoriasis. The information was based on patients who had been treated in hospital and may therefore have had more severe forms of the disease. Overall patients with psoriasis died at a younger age group than controls - 71 compared with 74.5 years. Death occurring in patients with psoriasis was more likely in those with psoriasis and diseases of the gastrointestine, the heart and circulatory system, lung and endocrine system. Psoriasis patients with metabolic disease, including obesity, as well as cancers in general were also at higher risk of death. There was a small increased risk of death in patients with psoriatic arthritis if the patients also had lung or some infectious diseases. Overall this study re-enforces previous work that has suggested that patients with the more severe forms of psoriasis have higher death rates than the general population.