tbuckley/cabot-search huggingface dataset:
Targeting of BCL2 Family Proteins with ABT-199 and Homoharringtonine Reveals BCL2- and MCL1-Dependent Subgroups of Diffuse Large B-Cell Lymphoma
Authors: Magdalena Klanova, Ladislav Andera, Jan Brazina, Jan Svadlenka, Simona Benesova, Jan Soukup, Dana Prukova, Dana Vejmelkova, Radek Jaksa, Karel Helman, Petra Vockova, Lucie Lateckova, Jan Molinsky, Bokang Calvin Lenyeletse Maswabi, Mahmudul Alam, Roman Kodet, Robert Pytlik, Marek Trneny, Pavel Klener
Journal: Clinical Cancer Research (2015)

To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL.By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL.As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.
Identification of autoantibodies to tumor-derived antigens as candidate biomarkers for the early detection of lung cancer
Authors: Wei-Min Gao, Eric Puravs, Rong Zhao, Bin Deng, Hong Wang, Ji Qiu, Rork Kuick, Robert Hinderer, David E. Misek, Gilbert S. Omenn, Samir M. Hanash
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4363 

Identification of tumor-associated antigens that induce auto-antibodies may have utility as serum biomarkers for the early detection of lung cancer. We have used a proteomic approach to identify proteins that commonly induce a humoral response in lung cancer. In this study, aliquots of solubilized proteins from the lung adenocarcinoma cell line NCI-H522 were subjected to 2-D PAGE, followed by Western blot analysis in which sera of individual subjects were tested for primary antibodies. Sera from 21 newly diagnosed patients with lung cancer, 14 patients with chronic obstructive pulmonary disease (COPD), and 21 healthy subjects were analyzed. Replicate analysis of the same sera yielded similar patterns of reactivity with individual protein spots. The integrated intensity measurements of reactive protein spots were computed following gel normalization using a set of reference protein spots. We applied a non-parametric test statistic that counts the number of cancer patients with values larger than the second largest value in the control group for statistical analysis of the data. Auto-antibodies against three proteins, identified by tandem mass spectrometry as 60S acidic ribosomal protein P0 (RPLP0), proteosome subunit beta 7 (PSMB7), and protein gene product 9.5 (PGP 9.5) met our criteria and were each detected in sera from 8/21 (38.1%) patients with lung cancer (p=0.01). Fourteen of 21 (66.7%) lung cancer sera reacted with at least one of these three proteins. In-gel global phosphoprotein and glycoprotein staining patterns revealed that the antigenic form of RPLP0 was phosphorylated, but not glycosylated. The antigenic isoforms of PSMB7 and PGP9.5 were not phosphorylated or glycosylated. Analysis of mRNA expression in human lung adenocarcinoma revealed no expression differences of RPLP0 and PSMB7 in comparison of stage 1 and stage 3 tumors, as compared to normal lung. PGP9.5, on the other hand, was found to be 5-fold over-expressed in stage 1, and 10-fold over-expressed in stage 3 lung adenocarcinoma, as compared to normal lung. PGP9.5 was previously found to exhibit similar reactivity using A549 lung carcinoma lysates, whereas RPLP0 and PSMB7 represent novel antigens in lung adenocarcinoma. Our study identified novel proteins that induce auto-antibodies in lung cancer. The development of a panel of such antigens may have utility for the early diagnosis of lung cancer and may have utility for immunotherapy.
The effect of palliative care consultations on the end-of-life care in the Veteran's cancer population.
Authors: W. Gonsalves, T. Tashi, I. Aldoss, M. Kalaiah, N. Didwaniya, S. Stenoien, C. Eberle, A. Ganti, S. Subbiah, P. T. Silberstein
Journal: Journal of Clinical Oncology (2010)

9080 Background: End-of-Life (EOL) care in terminally ill cancer patients has become increasingly aggressive over the past decade leading to poor quality of life. We analyzed the utilization of the palliative care services in terminally ill cancer patients to assess its effect on EOL care. Methods: We identified the last 100 cancer patients at our regional Veteran's Hospital who died in 2009. Independent chart reviews recorded the following variables: age, gender, race, date of diagnosis, date of death, date of palliative consult, date of hospice initiation, hospice duration and location of patient in the last 30 days of life. Results: Mean age was 71 years (range: 51-90). In the last 30 days of life, 18 patients received chemotherapy, 71 patients were hospitalized, 59 patients visited the ER and 33 patients were admitted to the ICU. Fifty eight patients received palliative care consults, 25 (43%) did so ≥ 2 weeks before death. Patients who received palliative care consults ≥ 2 weeks before death had fewer ICU admissions, ER visits, number of inpatient days and number of hospitalizations (Table). These patients were more often referred to hospice (76% vs. 38%, p <0.001), were less likely to die in the hospital (26% vs. 43%, p = 0.04) and less likely to spend ≤ 3 days in hospice before death (29% vs. 55%, p = 0.004). Conclusions: Majority of terminally ill veteran cancer patients received futile aggressive EOL care. Timely palliative care services improve the quality of EOL care and should be considered in every patient with metastatic cancer. Last 30 days of life Palliative consult ≥ 2 weeks before death Palliative consult < 2 weeks before death No palliative consult Number of patients 25 33 42 Received chemotherapy 3 (12%) 8 (24%) 7 (17%) >1 ER visit 0 (0%) 5 (15%) 4 (10%) Hospitalized >14 days 6 (24%) 16 (49%) 16 (33%) >1 hospital admission 2 (8%) 10 (30%) 4 (10%) ICU admission 6 (24%) 14 (42%) 13 (31%) < 3 days in hospice 4 (16%) 13 (39%) 23 (55%) Hospice consult 19 (76%) 25 (76%) 16 (38%) No significant financial relationships to disclose.
Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy
Authors: Frederick J. Kohlhapp, Howard L. Kaufman
Journal: Clinical Cancer Research (2015)

Abstract Oncolytic viruses are native or engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more efficient viral replication, and with selected deletion of specific viral genes, replication in normal cells with activated PKR may not be possible. Direct tumor cell lysis, release of soluble tumor antigens, and danger-associated molecular factors are all thought to help prime and promote tumor-specific immunity. Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type I and is the first oncolytic virus to demonstrate a clinical benefit in patients with melanoma. T-VEC has also been evaluated for the treatment of head and neck cancer, pancreatic cancer, and likely other types of cancer will be targeted in the near future. T-VEC has been modified for improved safety, tumor-selective replication, and induction of host immunity by deletion of several viral genes and expression of human granulocyte-macrophage colony stimulating factor. Although the mechanism of action for T-VEC is incompletely understood, the safety profile of T-VEC and ability to promote immune responses suggest future combination studies with other immunotherapy approaches including checkpoint blockade through PD-1, PD-L1, and CTLA-4 to be a high priority for clinical development. Oncolytic viruses also represent unique regulatory and biosafety challenges but offer a potential new class of agents for the treatment of cancer. Clin Cancer Res; 22(5); 1048–54. ©2015 AACR.
Costimulation to enhance the antitumor activity of CD19 eng T cells
Authors: Mireya Velasquez, David Torres, Aarohi Thakkar, Sunitha Kakarla, Carolyn Arber Barth, Xiao-Tong Song, Stephen Gottschalk
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immunotherapy with T cells or bispecific T cell engagers is one promising approach to improve outcomes for patients with CD19-positive hematological malignancies. We had previously shown that T cells expressing bispecific T cell engagers that recognize CD19 and CD3 (CD19-ENG T
Histone reader BRWD1 targets and restricts recombination to the Igk locus
Authors: Malay Mandal, Keith M Hamel, Mark Maienschein-Cline, Azusa Tanaka, Grace Teng, Jigyasa H Tuteja, Jeffrey J Bunker, Neil Bahroos, John J Eppig, David G Schatz, Marcus R Clark
Journal: Nature Immunology (2015)
Airborne formaldehyde causes skin barrier dysfunction in atopic dermatitis
Authors: J. Kim, Y. Han, J.H. Ahn, S.W. Kim, S.I. Lee, K.H. Lee, K. Ahn
Journal: British Journal of Dermatology (2015)

It remains to be elucidated whether exposure to air pollutants aggravates atopic dermatitis (AD). This study aimed to evaluate the effects of exposure to formaldehyde for 1 h and 2 h on skin barrier function in both the control and the AD groups. In 41 patients with AD and 34 healthy children, a provocation test was performed in which two different areas of normal‐appearing skin on the forearm were stimulated with airborne formaldehyde at 500 μg m−3 or placebo for 2 h. We measured transepidermal water loss (TEWL) and skin pH, and calculated the percentage change from baseline. Exposure to formaldehyde increased TEWL in the control group [P < 0·001; median of difference 1·4; interquartile range (IQR) 0·9–1·6] and in the AD group (P < 0·001; median of difference 2·5; IQR 2·0–3·6). The percentage change of TEWL after formaldehyde exposure in the AD group was higher than in the control group (P < 0·001), whereas exposure to placebo showed no differences between both groups. The AD group also demonstrated a higher percentage increase in skin pH after exposure to formaldehyde than the control group (P < 0·001). Short‐term exposure to formaldehyde causes skin barrier dysfunction in both healthy children and children with AD, and this effect is more prominent in children with AD.
Vaccination strategies for neuro-oncology: Table 1.
Authors: John H. Sampson, Duane A. Mitchell
Journal: Neuro-Oncology (2015)

Vaccination against cancer-associated antigens has long held the promise of inducting potent antitumor immunity, targeted cytotoxicity while sparing normal tissues, and long-lasting immunologic memory that can provide surveillance against tumor recurrence. Evaluation of vaccination strategies in preclinical brain tumor models has borne out the capacity for the immune system to effectively and safely eradicate established tumors within the central nervous system. Early phase clinical trials have established the feasibility, safety, and immunogenicity of several vaccine platforms, predominantly in patients with glioblastoma. Definitive demonstration of clinical benefit awaits further study, but initial results have been encouraging. With increased understanding of the stimulatory and regulatory pathways that govern immunologic responses and the enhanced capacity to identify novel antigenic targets using genomic interrogation of tumor cells, vaccination platforms for patients with malignant brain tumors are advancing with increasing personalized complexity and integration into combinatorial treatment paradigms.
Local compartment changes and regulatory landscape alterations in histone H1-depleted cells
Authors: Geert Geeven, Yun Zhu, Byung Ju Kim, Boris A. Bartholdy, Seung-Min Yang, Todd S. Macfarlan, Wesley D. Gifford, Samuel L. Pfaff, Marjon J. A. M. Verstegen, Hugo Pinto, Marit W. Vermunt, Menno P. Creyghton, Patrick J. Wijchers, John A. Stamatoyannopoulos, Arthur I. Skoultchi, Wouter de Laat
Journal: Genome biology (2015)

Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. It has been implicated in chromatin compaction and gene regulation and is anticipated to play a role in higher-order genome structure. Here we have used a combination of genome-wide approaches including DNA methylation, histone modification and DNase I hypersensitivity profiling as well as Hi-C to investigate the impact of reduced cellular levels of histone H1 in embryonic stem cells on chromatin folding and function.We find that depletion of histone H1 changes the epigenetic signature of thousands of potential regulatory sites across the genome. Many of them show cooperative loss or gain of multiple chromatin marks. Epigenetic alterations cluster to gene-dense topologically associating domains (TADs) that already showed a high density of corresponding chromatin features. Genome organization at the three-dimensional level is largely intact, but we find changes in the structural segmentation of chromosomes specifically for the epigenetically most modified TADs.Our data show that cells require normal histone H1 levels to expose their proper regulatory landscape. Reducing the levels of histone H1 results in massive epigenetic changes and altered topological organization particularly at the most active chromosomal domains. Changes in TAD configuration coincide with epigenetic landscape changes but not with transcriptional output changes, supporting the emerging concept that transcriptional control and nuclear positioning of TADs are not causally related but independently controlled by the locally associated trans-acting factors.
An immune surveillance model to monitor the response to neo-adjuvant chemotherapy treatment in breast cancer patients
Authors: David A Bernal-Estévez, Oscar A García, Ramiro Sanchez, Carlos A Parra-López
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Tumors treated with doxorubicin generates immunogenic cell death of tumor cells, favoring cross-presentation of tumor antigens by DCs to CD8 T cells conferring antitumor immunity in vaccinated mice. On the other hand, low-dose of cyclophosphamide reduces the number of regulatory T
ACC/AAP/AHA/ASE/HRS/SCAI/SCCT/SCMR/SOPE 2014 Appropriate Use Criteria for Initial Transthoracic Echocardiography in Outpatient Pediatric Cardiology
Authors: Robert M. Campbell, Pamela S. Douglas, Benjamin W. Eidem, Wyman W. Lai, Leo Lopez, Ritu Sachdeva
Journal: Journal of the American College of Cardiology (2014)
Molecular fine-tuning of affinity maturation in germinal centers
Authors: Yee Ling Wu, Cristina Rada
Journal: Journal of Clinical Investigation (2015)

The development of high-affinity antibodies in response to infection is an iterative process in which B cells cycle between proliferation/somatic hypermutation and antigen-driven selection. These processes occur within specific regions of the secondary lymphoid structures known as germinal centers (GCs) and the environmental and signaling cues provided by these regions guide the GC reactions that drive B cell maturation and antibody production, ultimately determining B cell fate. In this issue of the JCI, Nakagawa and colleagues examine the role of miR-155, a microRNA that is required for GC development and the production of high-affinity antibodies. They show that miR-155 is highly expressed in positively selected B cells and promotes survival of these cells by orienting the Myc transcription program toward survival rather than apoptosis through the inhibition of the transcriptional regulator JARID2. These findings illustrate the fine balance between apoptosis and proliferation that is required for the development of high-affinity antibodies.
Inhibitory Effect of Dietary &lt;italic&gt;p&lt;/italic&gt;-Methoxybenzeneselenol on Azoxymethane-Induced Colon and Kidney Carcinogenesis in Female F344 Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: B S Reddy, T Tanaka, K El-Bayoumy
Journal: JNCI Journal of the National Cancer Institute (1985)

The effect of dietary p-methoxybenzeneselenol on colon carcinogenesis induced by azoxymethane [(AOM) CAS: 25843-45-2] was studied in female F344 rats. Starting at 5 weeks of age, animals were fed the high-fat diet (control diet) or high-fat diet to which 50 ppm of p-methoxybenzeneselenol (experimental diet) had been added. At 7 weeks of age, all animals except the vehicle-treated controls were administered sc injections of AOM (15 mg/kg body wt, once weekly for 3 wk). Animals were fed the control and experimental diets until 1 week after carcinogen treatment when those animals receiving the p-methoxybenzeneselenol diet were fed the control diet until termination of the experiment, p-Methoxybenzeneselenol in the diet significantly inhibited the incidence (percentage of animals with tumors) of tumors in the colon and kidney, as well as the colon tumor multiplicity (adenomas and adenocarcinomas per animal).
DWIBS (diffusion weighted whole body imaging with background signal suppression) scan for colorectal cancer and its evaluation: Comparison with CT or PET scans
Authors: T. Sasatomi, Y. Ogata
Journal: Journal of Clinical Oncology (2009)

e15140 Background: The most important clinical point for the colorectal cancer patients after surgery is to find out local recurrence and distant metastasis to liver or lungs in early state. Recently, DWIBS (diffusion weighted whole body imaging with background body signal suppression) scan, one of the diffusion weighted MRI imaging methods, was developed, and it has been become used for diagnosis of lung cancer and bladder cancer instead of PET scan. In this report, we examined whether it was more useful method for the diagnosis of recurrence or distant metastasis of the colorectal cancer after surgery than PET/CT scan or not. Methods: All the 12 primary colorectal carcinomas were resected at the surgical division, Kumamoto Central Hospital, Fukuoka Saisekai Ohmuta Hospital and Kurume University Medical Center from 2000 to 2008. (Table 1) After surgery, 14 recurrent regions (seven liver metastasis, two lung metastasis and five local recurrence) were diagnosed by CT and MRI scans. Then all the cases were performed by DWIBS scan. And also the seven out of 12 cases (three liver metastasis, two lung metastasis and four local recurrence) were performed by PET scan. Conditions set before DWIBS scan were six hours of fasting with no restriction on drinking water and normal oral administration of regularly used drugs. No bowel preparation was carried out in any of the patients. Informed consent was obtained from each patient before DWIBS scan. Results: All the 14 metastatic and recurrent regions (seven liver metastasis, two lung metastasis and five local recurrence ) of 12 recurrent patients were performed by DWIBS, MRI and CT scans. Within the seven out of 12 recurrent patients (three liver metastasis, two lung metastasis and five local recurrence), performed by PET scan, all the liver and lung metastatic regions were detected, on the other hand, three out of four local recurrent regions were diagnosed but the other one was not diagnosed by PET scan. Conclusions: DWIBS is not only useful diagnostic method for local recurrence of colorectal cancer after surgery, but also less invasive method than PET scan. No significant financial relationships to disclose.
Defensin Promotes the Binding of Lipoprotein(a) to Vascular Matrix
Authors: Khalil Bdeir, William Cane, Gabriela Canziani, Irwin Chaiken, John Weisel, Marlys L. Koschinsky, Richard M. Lawn, Peter G. Bannerman, Bruce S. Sachais, Alice Kuo, Mark A. Hancock, John Tomaszewski, P.N. Raghunath, Tomas Ganz, Abd Al-Roof Higazi, Douglas B. Cines
Journal: Blood (1999)
Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial
Authors: J M Middeke, R Herbst, S Parmentier, G Bug, M Hänel, G Stuhler, K Schäfer-Eckart, W Rösler, S Klein, W Bethge, U Bitz, B Büttner, H Knoth, N Alakel, M Schaich, A Morgner, M Kramer, K Sockel, M von Bonin, F Stölzel, U Platzbecker, C Röllig, C Thiede, G Ehninger, M Bornhäuser, J Schetelig
Journal: Leukemia (2015)
Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127<sup>low</sup> Treg Cells in Patients With Chronic Rheumatoid Arthritis
Authors: Gina J. Walter, Veerle Fleskens, Klaus S. Frederiksen, Megha Rajasekhar, Bina Menon, Jens G. Gerwien, Hayley G. Evans, Leonie S. Taams
Journal: Arthritis & Rheumatology (2015)

Objective Conflicting evidence exists regarding the suppressive capacity of Treg cells in the peripheral blood (PB) of patients with rheumatoid arthritis (RA). The aim of this study was to determine whether Treg cells are intrinsically defective in RA. Methods Using a range of assays on PB samples from patients with chronic RA and healthy controls, CD3+CD4+CD25+CD127 low Treg cells from the CD45RO+ or CD45RA+ T cell compartments were analyzed for phenotype, cytokine expression (ex vivo and after in vitro stimulation), suppression of Teff cell proliferation and cytokine production, suppression of monocyte‐derived cytokine/chemokine production, and gene expression profiles. Results No differences between RA patients and healthy controls were observed with regard to the frequency of Treg cells, ex vivo phenotype (CD4, CD25, CD127, CD39, or CD161), or proinflammatory cytokine profile (interleukin‐17 [IL‐17], interferon‐γ [IFNγ], or tumor necrosis factor [TNF]). FoxP3 expression was slightly increased in Treg cells from RA patients. The ability of Treg cells to suppress the proliferation of T cells or the production of cytokines (IFNγ or TNF) upon coculture with autologous CD45RO+ Teff cells and monocytes was not significantly different between RA patients and healthy controls. In PB samples from some RA patients, CD45RO+ Treg cells showed an impaired ability to suppress the production of certain cytokines/chemokines (IL‐1β, IL‐1 receptor antagonist, IL‐7, CCL3, or CCL4) by autologous lipopolysaccharide‐activated monocytes. However, this was not observed in all patients, and other cytokines/chemokines (TNF, IL‐6, IL‐8, IL‐12, IL‐15, or CCL5) were generally suppressed. Finally, gene expression profiling of CD45RA+ or CD45RO+ Treg cells from the PB revealed no statistically significant differences between RA patients and healthy controls. Conclusion Our findings indicate that there is no global defect in either CD45RO+ or CD45RA+ Treg cells in the PB of patients with chronic RA.