tbuckley/cabot-search huggingface dataset:
Vaccine for cancer and infectious diseases.
Authors: Yucheng Tang, Hakan Akbulut, Jonathan Maynard, Line Petersen, Albert Deisseroth
Journal: Cancer Research (2007)

1847  Recent analyses of influenza vaccination clinical data shows that there is no survival advantage above the age of 55 and a 4 fold lower antibody response to the multivalent inactivated particle influenza vaccination in individuals over the age of 55. This poor response to vaccines may be due to decreased numbers of antigen naive CD8 and CD4 T cells, and the acquisition of functional defects in CD4 helper cells, like decreased expression of the CD40L in activated CD4 cells. In order to develop a method to overcome these defects in the immune response in older individuals, we have designed an adenoviral vector (Ad-sig-TAA/ecdCD40L) for the in vivo activation and tumor antigen loading of dendritic cells (DCs). This adenoviral vector encodes a fusion protein composed of an aminoterminal tumor associated antigen (TAA) fragment fused to the extracellular domain (ecd) of the CD40 ligand (CD40L) at the carboxyl terminal end. Two sc injections of this vector have broken tolerance to specific tumor associated antigens in two separate TAA.Tg transgenic mouse models (mice transgenic for rat Her-2-Neu (rH2N) and human MUC-1 (hMUC-1)). Her-2-Neu and MUC-1 are tumor associated antigens which are overexpressed in poor prognosis epithelial neoplasms such as adenocarcinomas of the breast , prostate, ovary, colon and lung. The immunoprotection extends for over a year and is independent of CD4 cells. We showed that the sc injection of the hMUC-1/ecdCD40L protein following the sc injection of the Ad-sig-TAA/ecdCD40L vector (this vector prime-protein boost is called VPP) increases the levels of both the cellular and humoral immune response over that achievable with just the vector injections alone in the hMUC-1.Tg mice. The antibodies from hMUC-1 VPP vaccinated mice bind to biopsy specimens of human cancers of the breast and prostate. Importantly, the VPP vaccination can induce an immune response even in 18 month old mice which completely suppresses tumor growth in old (18 month old) mice. The Ad-sig-rH2N/ecdCD40L vaccination suppresses the evolution of spontaneous breast cancer in the rH2N.Tg mouse model. We also tested the immune response induced by the Ad-sig-HA/ecdCD40L vector prime-HA/ecdCD40L protein boost which is directed to the H5N1 hemagglutinin (HA) antigen and the Ad-sig-M2/ecdCD40L vector prime-M2/ecdCD40L protein boost vaccine against the M2 antigen, which has a common sequence among human and avian influenza strains. Both induced a robust cellular and humoral response in old (18 month) mice as well as in young (2 month) mice. The serum of mice vaccinated with 3 sc injections of HA/ecdCD40L contained neutralizing antibodies against the H5N1 486 avian influenza virus at 1/4000 dilution of the serum. The Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost strategy may be of value in the prevention and treatment of cancer and infectious diseases.
Abstract #4925: Unique role for the Rb LxCxE binding domain in lung development
Authors: Mohammad Ahmad, Zhen Huang, Fred Dick, Martin Post, Colin McKerlie, Rod Bremner
Journal: Cancer Research (2009)

The retinoblastoma tumor suppressor protein (Rb) regulates cell division, death and differentiation. Loss of Rb causes retinoblastoma in humans. Previously we developed a mouse model of retinoblastoma using conditional knockout of Rb because germline Rb deletion is lethal. Rb exon 19 is floxed and retinal-specific deletion is driven by \#945;-Cre (\#945;-CreRbf/f). The developing Rb null retina (\#945;-CreRbf/f) shows ectopic cell division and death of certain neurons in the developing retina. Loss of both Rb and its relative p107 (\#945;-CreRbf/f;p107-/-) lead to more extensive ectopic division and additional phenotypes of cone death and tumorigenesis. Rb binds E2f transcription factors and regulates their activity. While bound to E2fs, Rb can also recruit corepressors, many of which have a unique LxCxE motif (L-Leucine, C-Cysteine, E-Glutamate, and X-any amino acid) which binds the LxCxE-binding domain (LBD) of Rb. The role of LxCxE-motif proteins (LMPs) corepressors in mediating Rb function in vivo is unknown. We hypothesized that they may be critical for only a subset of Rb activities. Thus, we used mice with a defective LBD (Rb\#916;), which cannot bind most LMPs, to define LxCxE-corepressor-dependent Rb activities in the retina. One (\#945;-CreRbf/\#916; ) or two (Rb\#916;/\#916;) Rb\#916; alleles suppressed the ectopic division and neuronal apoptosis seen in the Rb null (\#945;-CreRbf/f) retina, although low levels of apoptosis were detected at post natal day 18 (P18). In the absence of p107 and one Rb\#916; alleles (\#945;-CreRbf/\#916;;p107-/-), abnormal cell division and death were partially and tumorigenesis was completely suppressed. Importantly, Rb\#916;/\#916;;p107-/- mice did not survive beyond P0-P1 because of extensive lung hyperplasia, but did not show ectopic division or death in the retina. Collectively, these data suggest that recruitment of LMP corepressors by Rb is dispensable for promoting cell cycle exit and survival in the retina, but regulates lung development. Acknowledgement: This study was supported by grants from CIHR and Foundation Fighting Blindness Canada.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4925.
Antibodies targeting sialyl Lewis A mediate tumor clearance through distinct effector pathways
Authors: Polina Weitzenfeld, Stylianos Bournazos, Jeffrey V. Ravetch
Journal: Journal of Clinical Investigation (2019)

Sialyl Lewis A (sLeA, also known as CA19-9), a tetrasaccharide selectively and highly expressed on advanced adenocarcinomas including colon, stomach, and pancreatic cancers, has long been considered as an attractive target for active and passive vaccination. While progress in antibodies targeting tumor-associated protein antigens resulted in an impressive array of therapeutics for cancer treatment, similar progress in exploiting tumor-associated carbohydrate antigens, such as sLeA, has been hampered by the lack of a detailed understanding of the singular characteristics of these antigens. We have addressed this issue by analyzing antibodies derived from patients immunized with an sLeA/KLH vaccine. These antibodies were engineered to mediate tumor clearance in vivo in preclinical models through Fc-FcγR interactions. However, in contrast to protein antigens in which hFcγRIIIA engagement was both necessary and sufficient to mediate tumor clearance in both preclinical and clinical settings, a similar selective dependence was not seen for anti-sLeA antibodies. Thus, re-engineering the Fc portion of sLeA-targeting antibodies to broadly enhance their affinity for activating FcγRs led to an enhanced therapeutic effect. These findings will facilitate the development of more efficient anticancer therapies and further advance this promising class of therapeutic antibodies into clinical use.
Adaptation of host transmission cycle during Clostridium difficile speciation
Authors: Nitin Kumar, Hilary P. Browne, Elisa Viciani, Samuel C. Forster, Simon Clare, Katherine Harcourt, Mark D. Stares, Gordon Dougan, Derek J. Fairley, Paul Roberts, Munir Pirmohamed, Martha R. J. Clokie, Mie Birgitte Frid Jensen, Katherine R. Hargreaves, Margaret Ip, Lothar H. Wieler, Christian Seyboldt, Torbjörn Norén, Thomas V. Riley, Ed J. Kuijper, Brendan W. Wren, Trevor D. Lawley
Journal: Nature Genetics (2019)
Authors’ reply
Authors: Kathryn Oakland, Jonathan Hoare
Journal: Gut (2019)

We thank Dr Leeds et al for their interest and comments1 on the British Society of Gastroenterology guideline on the diagnosis and management of acute lower gastrointestinal bleeding (LGIB).2 They are quite correct to highlight the difference in evidence supporting therapeutic endoscopy in LGIB as opposed to upper. There is only one randomised trial that directly compared timing of colonoscopy in patients hospitalised with LGIB, which as the authors’ state demonstrated no difference in clinical outcomes, however, the trial was terminated before the required sample size had been reached.3 Pooled analysis in a systematic review of non-randomised studies demonstrated that early colonoscopy was associated with higher diagnostic and therapeutic yields and most importantly a shorter length of …
25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303.
Authors: Katherine Van Loon, Kouros Owzar, Chen Jiang, Hedy Lee Kindler, Mary Frances Mulcahy, Donna Niedzwiecki, Eileen Mary O'Reilly, Charles S. Fuchs, Federico Innocenti, Alan Paul Venook
Journal: Journal of Clinical Oncology (2013)

4022 Background: Data from animal and cell line models suggest that vitamin D metabolism is important in pancreatic tumor maintenance and may contribute to this tumor’s chemoresistance. While vitamin D has been implicated in a variety of cancers, the prevalence of vitamin D deficiency among patients with advanced pancreatic cancer (APC) and the effect of baseline vitamin D levels on survival outcomes are unknown. Methods: CALGB 80303 was a randomized controlled trial of patients with APC which demonstrated no difference in OS among patients treated with gemcitabine (GEM) vs. GEM + bevacizumab. We retrospectively measured baseline serum 25(OH)D levels and examined associations between baseline 25(OH)D levels and selected patient characteristics. Using the Cox rank score test, we examined the association between 25(OH)D level and PFS and OS. The differences in the levels among racial populations were tested using the Kruskal-Wallis test. Results: Of 256 patients with available serum, the median 25(OH)D level was 21.7 (range 4–77). 44.5% of patients were vitamin D deficient (25(OH)D &lt;20), 32.4% were insufficient (25(OH)D ≥20 and &lt;30), and 23% were sufficient (25(OH)D≥30). Serum 25(OH)D levels were lower in patients self-reported as black compared to white patients and patients of other/undisclosed race (median 10.7 [4.0–36.3] vs. 22.4 [4.0–77.0] vs. 20.9 [12.6 – 31.8], respectively; p&lt;0.00001). Adjusting for race, baseline 25(OH)D levels were not associated with PFS (HR 1.00, 95% CI 0.98–1.01) or OS (HR 1.00, 95% CI 0.99-1.01). Conclusions: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of APC. Black patients had significantly lower 25(OH)D levels than white patients. In this cohort of patients with APC receiving GEM-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.
Treatment Characteristics and Outcomes for Newly Diagnosed Elderly Patients with Acute Myeloid Leukemia (AML) Treated in the United States with Either 7+3 or a Hypomethylating Agent (HMA)
Authors: Jill A Bell, Aaron Galaznik, Eileen Farrelly, Sharanya Murty, Augustina Ogbonnaya, Michael T. Eaddy, Robert J. Fram, Douglas V. Faller, Vamsi Kota
Journal: Blood (2017)
Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer (ca).
Authors: Kenneth J. Chang, Neil N. Senzer, Kenneth Binmoeller, Howard Goldsweig, Robert Coffin
Journal: Journal of Clinical Oncology (2012)

e14546 Background: T-VEC is an investigational, immune-enhanced oncolytic herpes simplex virus type I that selectively replicates in solid tumors. This was an open-label, dose-escalation study of T-VEC administered by endoscopic ultrasound (EUS)-guided fine needle injection (FNI) for advanced pancreatic ca. Methods: Eligibility criteria included ≥ 18 yrs old, ECOG 0-2, pathologically confirmed pancreatic ca with measurable disease (tumors ≥ 1 cm dia), and failure or unable to receive standard tx. T-VEC was administered at wks 6, 12, 18 to a single pancreatic tumor in 4 cohorts (C), 3 pts each enrolled sequentially (extended dosing allowed in pts thought to have benefit): C 1: 1 dose of 10 4 PFU/mL then 2 of 10 5 PFU/mL; C 2: 1 dose of 10 5 PFU/mL then 2 of 10 6 PFU/mL; C 3: 1 dose of 10 6 PFU/mL then 2 of 10 7 PFU/mL; C 4: 1 dose of 10 6 PFU/mL then 2 of 10 8 PFU/mL. 2 doses/pt were required for enrollment to the next C. A C could be expanded to 6 if 1 related DLT occurred. If 2 DLTs occurred, dose escalation was stopped. Endpoints were safety and activity as assessed by CT tumor dia changes from screening. Results: 17 pts were enrolled in C 1-3 given at least 1 dose of T-VEC; 65% were men; median age 54; 76% white, ECOG 0-1 82%. C 4 was not opened because of early study termination (not related to safety). 7/17 (41%) received all 3 planned doses and 8 (47%) had at least 1 post-dose CT scan. Only C 3 showed a median decrease in injected tumor dia with 2/4 pts achieving substantial tumor reductions (-36% and -33%). 3 pts (in C 1and C 3) showed decreases in the dia of ≥ 1 uninjected tumors (in liver, pancreas, kidney, and chest); 1 pt had disappearance of a nonmeasurable tumor in the liver. A dose trend was not observed for reductions of uninjected tumors. Most common AEs were ascites (47%), dehydration (41%), anemia, abdominal pain, constipation, and nausea (each 35%), and vomiting (29%). 2 pts (12%) had a grade 5 AE, both considered unrelated to T-VEC. Conclusions: EUS-guided FNI of T-VEC in advanced pancreatic ca, at initial doses of 10 4 to 10 6 PFU/mL followed by up to 10 7 PFU/mL, was feasible and tolerable. Evidence of biologic activity was observed. Future studies should be conducted in pts with less advanced disease, to allow sufficient time to receive multiple doses before PD.
Abstract #1683: mTOR pathway inhibition via folate receptor specific delivery of the folate-everolimus conjugate EC0565
Authors: Nikki Parker, Alicia Bloomfield, Kristen Emsweller, Melissa Nelson, Joseph Reddy, Christopher Leamon
Journal: Cancer Research (2009)

The discovery that expression of the membrane-bound, high affinity folate receptor (FR) occurs in a significant number of human malignancies has led to the development of many folate-targeted therapeutic agents. Studies in FR-positive tumor models have demonstrated remarkable anti-tumor activity of various folate-drug conjugates under conditions that do not appreciably cause toxicity. The ability to chemically link a variety of drugs to folate offers an array of choices for targeting different proteins and biochemical pathways within the FR-positive cell. For example, it is known that aberrations in mTOR pathway signaling can lead to the development and progression of many cancers and inflammatory diseases. Likewise, mTOR inhibitors, such as rapamycin and everolimus, have been studied extensively and have been clinically shown to exhibit immunosuppressive and anti-neoplastic effects. Here, we have investigated the ability of a novel folate-everolimus conjugate, named EC0565, to reduce the levels of phospho-ribosomal protein S6 (p-RPS6, a translation-regulating protein downstream of mTOR) in a panel of cell lines. The results of our studies demonstrated that EC0565 potently inhibited p-RPS6 (EC50 = 8.2 nM) in the high FR-expressing KB cell line; further, the activity of EC0565 was completely blocked at each dose level with a co-incubated excess of a benign folate analog, thus indicating that EC0565\#8217;s activity was FR-specific. We also observed a strong correlation between the level of FR expression and the ability of EC0565 to inhibit p-RPS6. For example, whereas 100 nM EC0565 caused near complete abrogation of p-RPS6 in KB cells, and substantial or measurable activity in IGROV and SKOV3 cell lines, levels of p-RPS6 were unaffected in the FR-negative A549 cell line. Importantly, when A549 cells were treated with untargeted everolimus, p-RPS6 was completely inhibited indicating that lack of activity with EC0565 was not due to lack of base drug activity against A549 cells. Kinetically, EC0565 activity lagged behind that of everolimus (t1/2 = 1.3 h and 0.48 h, respectively), which is in concordance with a FR-mediated, endocytic delivery mechanism. Despite the significant FR-specific activity observed at the molecular level, proliferative activity of KB cells was unaffected by either EC0565 or everolimus in vitro. However, some modest anti-tumor activity (i.e. tumor growth delay) was observed with a 3 \#956;mol/kg qdx5 dosing regimen against the KB xenograft tumor model in nude mice. Collectively, these data demonstrate that EC0565 blocks mTOR pathway activity by a FR-dependent mechanism, and they support further study with other FR-expressing cell/tumor models, especially in those that are proliferation-sensitive towards mTOR inhibition.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1683.
Mycoplasma infection suppresses p53 function and cooperates with oncogenic Ras in fibroblast transformation
Authors: Denis Logunov, Dmitry Scheblyakov, Irina Rakovskaya, Boris Naroditsky, Alexander Ginzburg, Andrei Gudkov
Journal: Cancer Research (2007)

5012  Prokaryotes of the genus Mycoplasma are the smallest cellular organisms that persist as obligate extracellular parasites. Although mycoplasma infection is known to be associated with chromosomal instability and can promote malignant transformation, the mechanisms underlying these phenomena remain unknown. Since persistence of many cellular parasites requires suppression of the mechanisms of apoptosis in host cells, we tested the effect of mycoplasma infection on the activity of p53 pathway, one of the major mechanisms of programmed cell death involved in control of genomic stability. To monitor the activity of p53 in mycoplasma-infected cells, we used human colon (HCT-116) and breast (MCF-7) carcinoma cell lines bearing beta-galactosidase reporter gene under the control of a p53-responsive promoter. The cells were infected with different species of mycoplasma (M. arginini, M. orale, M. pneumoniae, M. hominis, M. fermentas, U. urealiticum and A. laidlawii) and p53 transactivation ability was compared between infected and non-infected cells. In general, the activity of p53 was reduced in mycoplasma infected cells with M. arginini being the strongest suppressor of p53 among those tested. Consistently, the expression of p21waf1 protein, a p53-responsive gene, was decreased in mycoplasma-infected cells. Importantly, infection with M. arginini made non-transformed rat embryo fibroblasts REF52 susceptible to transformation with oncogenic H-Ras, while non-infected REF52 cells underwent irreversible p53-dependent growth arrest. Mycoplasma-infected cells were as permissive to Ras-induced transformation as REF52 with p53 knockdown by inhibitory shRNA. These observations indicate that Mycoplasma infection plays the role of a p53 suppressing oncogene that cooperates with Ras in cell transformation and suggests the carcinogenic and mutagenic effects of mycoplasma can be mediated by the suppression of p53 tumor suppressor function by the parasite.
SAHA (Histone deacetylase inhibitor) enhanced 5-FU sensitivity by downregulation of TS (Thymidylate Synthase) expression in lung cancer cells.
Authors: Rintaro Noro, Akihiko Gemma, Akihiko Miyanaga, Hideaki Mizutani, Tsuneo Shimokawa, Hidehiko Kuribayashi, Tetsuya Okano, Masahiro Seike, Kiyoko Kataoka, Kuniko Matsuda, Yuji Minegishi, Michiya Nara, Akinobu Yoshimura, Shoji Kudoh
Journal: Cancer Research (2008)

728  Several HDAC inhibitors including SAHA, are show promosing antitumor activity. Here ,we report these synergistic effect with 5-FU therapy in lung cancer cells. Using the MTT assay , we analyzed the growth-inhibitory effect of 5-FU and SAHA against 8 lung cancer cell lines. The mRNA and protein of TS,DPD,OPRT and TP, which have been reported related to 5-FU sensitivity and resistance , were analyzed in these lines. One 5-FU-sensitive line had no DPD expression, and seven 5-FU resistant lines had TS and DPD overexpression. Combined treatment with low dose SAHA enhanced 5-FU mediated cytoxicity in 5-FU-resistant cells. SAHA downreguleted TS mRNA , protein and increased their expression followed by 5-FU treatment . In orde to clarify the mechanism of downregulation of TS mRNA expression, we are examining the promoter states of TS gene related histone acetylation and E2F-1 transcript activity.  We conclude that a combination therapy using HDAC inhibitor and 5FU may be useful at overcoming 5-FU resistance in lung cancer.
Trends in Medical Aid in Dying in Oregon and Washington
Authors: Luai Al Rabadi, Michael LeBlanc, Taylor Bucy, Lee M. Ellis, Dawn L. Hershman, Frank L. Meyskens, Lynne Taylor, Charles D. Blanke
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The combined 28 years of data of medical aid in dying (MAID) between Oregon (OR) and Washington (WA) are the most comprehensive in North America. No reports to date have compared MAID use in different US states. <h3>Objective</h3> To evaluate and compare patterns of MAID use between the states with the longest-running US death with dignity programs. <h3>Design, Setting, and Participants</h3> A retrospective observational cohort study of OR and WA patients with terminal illness who received prescriptions as part of their states' legislation allowing MAID. All published annual reports, from 1998 to 2017 in OR and from 2009 to 2017 in WA, were reviewed. A total of 3368 prescriptions were included. <h3>Main Outcomes and Measures</h3> Number of deaths from self-administration of lethal medication vs number of prescriptions written. <h3>Results</h3> A combined 3368 prescriptions were written in OR and WA, with 2558 patient deaths from lethal ingestion (76.0%). Of the 2558 patients, most were male (1311 [51.3%]), older than 65 years (1851 [72.4%]), and non-Hispanic white (2426 [94.8%]). The most common underlying illnesses were cancer (1955 [76.4%]), neurologic illness (261 [10.2%]), lung disease (144 [5.6%]), and heart disease (117 [4.6%]). Loss of autonomy (2235 [87.4%]), impaired quality of life (2203 [86.1%]), and loss of dignity (1755 [68.6%]) were the most common reasons for pursuing MAID. Time between drug intake to coma ranged from 1 to 660 minutes and time from drug intake to death ranged from 1 to 6240 minutes. In the 1557 patients for whom rates of complications were reported, 1494 (96.0%) did not experience a complication (592 of 626 [94.6%] in OR and 902 of 931 [96.8%] in WA). Eight patients (&lt;0.5%) regained consciousness after drug ingestion in OR. Annual rates per year for percentage of patients who received a prescription ingesting the prescribed medication ranged from 48% to 87%, with no significant time trend in OR (adjusted odds ratio per year, 1.01; 95% CI, 0.99-1.02;<i>P</i> = .59) but with an increase over time in WA (adjusted odds ratio per year, 1.13; 95% CI, 1.08-1.19;<i>P</i> &lt; .001). In both OR and WA there were increases in the number of patient deaths due to MAID per 1000 deaths over time. <h3>Conclusions and Relevance</h3> In this study, MAID results in Oregon and Washington were similar, although MAID use measured as a percentage of patients prescribed lethal medications and then self-administering them increased only in WA. Most patients who acquired lethal prescriptions had cancer or terminal illnesses that are difficult to palliate and lead to loss of autonomy, dignity, and quality of life.