tbuckley/cabot-search huggingface dataset:
Immunotransplant for mantle cell lymphoma: Phase I/II study preliminary results.
Authors: J. Brody, R. Advani, W. Weng, D. Czerwinski, A. A. Alizadeh, H. E. Kohrt, R. Negrin, R. Levy
Journal: Journal of Clinical Oncology (2011)

2509 Background: Mantle cell lymphoma (MCL) has a poor long-term prognosis. Though autologous transplant prolongs survival, novel therapies are needed to target the residual, myeloablation-resistant tumor cells that cause relapse. CpG-based vaccination can induce both anti-tumor T cells and clinical responses in low grade lymphoma patients [Brody J et al, JCO 2010]. Thus, we developed an immunotransplant maneuver combining: 1) CpG-based vaccination, 2) harvest of T cells, and 3) myeloablation followed by reinfusion of the vaccine-primed T cells. The anti-tumor T cells proliferate selectively, curing established lymphoma in a murine model [Brody J et al, Blood 2009]. Methods: Based on the preclinical model, we initiated a phase I/II study of immunotransplant for patients with newly diagnosed MCL. The primary endpoint is measurement of anti-tumor T cells at each phase of the maneuver. Anti-tumor T cells are defined as those which produce effector molecules (e.g. IFNγ, TNF, IL2, CD137, perforin and granzyme) upon co-culture with autologous tumor. A secondary endpoint is measurement of molecular residual disease (MRD) by ASO qPCR; the study is powered to detect a 50% improvement in sustained molecular remission rate compared to standard transplant [Pott C et al, Blood 2010, Geisler C et al, Blood 2008]. Results: We have enrolled 21 patients in the first 18 months. To date, 13 patients have completed the immunotransplant protocol, demonstrating feasibility and safety. All treated patients remain in clinical remission and 83% have shown amplification of anti-tumor T cells post-immunotransplant. Notably, we observe differing patterns of anti-tumor T cells amongst these patients, some having CD8 T cell responses, some with CD4 responses, and some with a combination. Conclusions: Immunotransplant amplifies anti-tumor T cells in a preclinical model and correlates with cure of myeloablation-resistant disease. The reiteration of such anti-tumor T cell amplification in our clinical trial raises the possibility that immunotransplant may improve clinical outcomes. MRD testing should indicate which T cell response patterns correlate with clinical benefit and whether the cohort has a better-than-expected molecular remission rate.
Utility of Prophylactic Autologous Stem Cell Collection for Patients with Acute Myeloid Leukemia in First Remission.
Authors: Margie Kasner, Selina Luger, Edward Stadtmauer, Stephen Schuster, Donald Tsai, Sunita Nasta, Alexander Perl, Alison Loren, Steven Goldstein, Patricia Mangan, Robert Sachs, Donald Seigel, David Porter
Journal: Blood (2004)
Abstract 1107: In whole-exome sequencing analysis, alternations of P-selectin glycoprotein ligand 1 (SELPLG) significantly associates with inflammation and survival outcomes
Authors: Sunghoon Cho, Chansu Lee, Hyun Choi, Kwang-Sung Ahn, Yongil Koh, Sung-Soo Yoon
Journal: Cancer Research (2015)

Abstract SELPLG is type I transmembrane receptor found on the surface of neutrophils, monocytes, and most lymphocytes. SELPLG interacts with P -selectin mediates the tethering and rolling of neutrophils, monocytes, and/or lymphocytes on endothelial cells. In whole exome sequencing analysis, we found that somatic mutation of SELPLG (2%) was found. Also its alternation (37%) was found in germline control group. rs201851784 of SELPLG polymorphism (43%) was determined in 118 adult AML patients and its polymorphism (12%) was determined in 1000 genome. The prevalence of the rs201851784 polymorphism was significantly different between AML patients and normal control (AA genotype vs. GG + AG genotype). Comparison analysis of SELPLG showed X-squared = 208.4140, df = 1 and p &amp;lt; 2.2e-16. After the IL-6 expression levels among AML patients were detected by ELISA, the allelic status and IL-6 expression on bone marrow serum of AML patients were analyzed. AML patient having A/G alternation was found to be associated with lower levels of IL-6 compared with AML patients having A/A. Those with persistence had higher IL-6 expression levels compared with those with CR in 1st induction (P &amp;lt; 0.05). In addition, there is a significant correlation between levels and SELPLG rs201851784, as analyzed by linear correlation assay. The AA genotype correlated with higher IL-6 levels (P &amp;lt; 0.05). Reverse correlation between SELPLG rs201851784 and IL-6 levels was found. SELPLG rs201851784 and IL-6 levels were also significantly correlated with OS. In conclusion, a polymorphism in the SELPLG gene related to cell dissemination and tissue infiltration is shown for the first time to be associated with susceptibility of AML and the overall survival. Citation Format: Sunghoon Cho, Chansu Lee, Hyun Choi, Kwang-Sung Ahn, Yongil Koh, Sung-Soo Yoon. In whole-exome sequencing analysis, alternations of P-selectin glycoprotein ligand 1 (SELPLG) significantly associates with inflammation and survival outcomes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2015-1107
Efficacy Of Dasatinib Therapy In Patients With Imatinib-Resistant Or -Intolerant Chronic Myeloid Leukemia From Physician’s and Patient’s Perspective: “Real World” Data
Authors: Tatyana I Ionova, Tatyana P Nikitina, Taras A Gritsenko, Valentina L Ivanova, Galina B Kuchma, Tatyana V Shnaider, Inga V Sannikova, Denis A Fedorenko, Kira A Kurbatova
Journal: Blood (2013)
Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice
Authors: Zhu-Fei Guan, Xiu-Ling Zhou, Xiao-Ming Zhang, Yu Zhang, Yan-Mei Wang, Qi-Lin Guo, Gang Ji, Guo-Feng Wu, Na-Na Wang, Hao Yang, Zhong-Yu Yu, Hou-Guang Zhou, Jing-Chun Guo, Ying-Chao Liu
Journal: Translational Neurodegeneration (2016)

Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process.High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy.1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups.Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.
692. A Novel RNAi Trigger Design Retains Potent, Target Specific Activity Despite Emerging Mutations in the Target Site
Authors: Ulrike Jung, Daniela Castanotto, Marc Jung, John Burnett, John J. Rossi
Journal: Molecular Therapy (2015)

Conventional si/shRNA designs are restricted to Watson/Crick pairing between guide strand and target RNA as this has been deemed crucial for potent Argonaute 2 based slicer activity. Despite individual publications partially challenging the requirement of sole Watson/Crick pairing these results have not yet found entry into RNAi designs. By rational incorporation of results from RNA crystallography structures and non-canonical and non-Watson/Crick pairings (nWCp) at certain positions we have developed a novel RNAi trigger design. Our approach allowed us to create shRNAs where a single guide strand suppresses a spectrum of target sequences through Argonaute 2 activity with target specificity, and similar or higher potency than a conventional design. Genomic off target effects were not observed in NGS analysis. In target/guide variant analysis several guide strands demonstrated potent RNAi activity even with G/U pairings at numerous positions or G/G pairings at position 10 or 11. Furthermore we demonstrate that this approach allows the application of RNAi against mutating targets as verified against HIV-1. Thus, our results demonstrate that an RNAi trigger can be applied to any therapeutic target (with an accessible RNA) prone to mutation-based resistance/escape offering significant improvement to the therapeutics of both infectious diseases and cancer. Additionally, we provide evidence that target and off-target prediction rules for microRNAs and shRNA/siRNAs may benefit from revisions to include a significantly wider set of pairings.
Patterns of care and survival in cancer patients with cognitive impairment
Authors: L. J. Callen, P. Vranas, J. Overcash, D. Boulware, M. Extermann
Journal: Journal of Clinical Oncology (2004)

8083 Background: Literature on survival patterns of geriatric patients with cancer and cognitive impairment is scant. The existing analects reveal cancer patients with cognitive impairment have twice the mortality of their non-impaired counterparts. The reason for the high mortality rates is unclear. There is an obvious need for clinical research to guide oncologists in the treatment of these patients. Methods: We conducted a retrospective case-control study in geriatric oncology patients aged 70 and older. Patients seen in Moffitt's Senior Adult Oncology Program (SAOP) presenting at initial CGA a MMSE of 24 or less were paired with patients presenting a MMSE of 25 or higher. Patients were matched for tumor type and stage. Baseline criteria were obtained from the SAOP prospective cohort database. Patterns of care and morbidity outcomes (PFS, OS) were obtained from Moffitt Cancer registry. Data were adjusted for baseline ECOG PS, ADL/IADL, CIRS - G and Charlson scores, GDS, age and sex with a Cox regression model. Results: Ninety-four cognitively impaired patients and 199 controls were included. Significant differences were found in survival rates and other assayed variables. At baseline cognitively impaired patients had worse PS (mean 1.4 vs. 0.49), were more dependent in ADL (median 1 vs.0) and IADL (mean 20.5 points vs. 26.7). A higher proportion of them screened as depressed (49% vs. 12%). They also had more severe comorbidities. Evaluated treatments were surgery, radiation, hormonal and chemotherapy. There were no major differences in the percentages of cases that received chemotherapy versus the controls. Median survival (272 pts) was 41.8 months in cognitively impaired and 95.3 months in the controls. Only 44% of the cases were living five years after treatment versus 63% of the controls (all p - values < 0.0001). The respective weights of the various health parameters on outcomes will be presented at ASCO. Conclusion: The cognitively impaired have worse survival duration than the controls. Nevertheless the cognitively impaired can expect to live on average 3.5 years. These results suggest that there is a significant potential for intervention in cognitively impaired cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Alternation in the Flutter Wave Morphology During Radiofrequency Catheter Ablation for Common Atrial Flutter
Authors: Kaoru Okishige, Kouji Azegami, Takako Satoh, Yoshinari Goseki, Hiroshi Ohira, Katsuhiro Yamashita, Shutarou Satake
Journal: Circulation (1998)

A linear lesion created at the right atrial isthmus by radiofrequency current application can successfully eliminate common atrial flutter (AF). The mechanism of unsuccessful cases has not yet been well delineated. This study sought to investigate the cause of unsuccessful cases of radiofrequency catheter ablation of AF. Sixty-six patients with refractory common AF were referred for radiofrequency catheter ablation. Radiofrequency current was applied to the right atrial isthmus between the inferior vena cava and tricuspid annulus or between the coronary sinus orifice and tricuspid annulus. In 5 (8%) of the 66 patients, a morphological change of the flutter wave was observed in the 12-lead ECG concomitant with the change of the atrial excitation sequence during the delivery of radiofrequency energy without the termination of atrial flutter. In 8 (12%) patients, the morphology of the new AF wave, which was provoked electrically after the termination of the original AF, was different, and the average flutter cycle length also differed in 3 cases (2%). The results of radiofrequency application could be misinterpreted as unsuccessful when the occurrence of another, different type of AF has been overlooked following the elimination of the original AF during the radiofrequency catheter ablation procedure. It is possible that the flutter circuit can take an alternative pathway despite the complete conduction block at the right atrial isthmus.
THP-COP Regimen for the Treatment of Peripheral T Cell Lymphoma and Adult T Cell Leukemia/Lymphoma: A Multicenter Phase II Study
Authors: Yasushi Takamatsu, Junji Suzumiya, Atae Utsunomiya, Koichi Maeda, Hitoshi Matsuoka, Hitoshi Suzushima, Junichi Tsukada, Kazuo Tamura
Journal: Blood (2008)
Development Of a Comprehensive Rapid Next-Generation Sequencing Assay For The Diagnosis Of Inherited Hemolytic Anemia
Authors: Amber Hogart Begtrup, Neha Dagaonkar, Suvarnamala Pushkaran, Katie M. Giger, Ammar Husami, Diane Kissell, Clinton H. Joiner, Mehdi Keddache, Kejian Zhang, Theodosia A. Kalfa
Journal: Blood (2013)
Vaccination of metastatic prostate cancer patients using mature dendritic cells transfected with mRNA encoding hTERT or an MHC class II targeted hTERT/LAMP fusion protein: Results from a phase I clinical trial
Authors: Z. Su, J. W. Vieweg, J. Dannull, P. Dahm
Journal: Journal of Clinical Oncology (2004)

2507 Background: hTERT, human telomerase reverse transcriptase, is overexpressed in 90% of all solid tumors and therefore represents a prime target for cancer immunotherapy. We have recently shown that hTERT RNA-transfected DC represent potent stimulators of hTERT-specific T cells and anti-tumor activity in vitro and in in vivo models. Based on these observations, we conducted a phase I clinical trial evaluating this strategy in patients with hormone-refractory prostate cancer. Methods: DCs were administered by intradermal injection of 1x107 cells in weekly intervals with total of 3 or 6 doses. In parallel, a cohort of patients received DC transfected with an RNA encoding a chimeric hTERT/LAMP protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses. Results: Results from 18 vaccinated patients have revealed no dose-limiting or adverse effects in any patients. After vaccination with hTERT or hTERT/LAMP RNA-transfected DC, high frequencies of hTERT-specific CD8+ and CD4+ T cells was observed in all subjects. Vaccination was associated with both molecular clearance of circulating tumor cells in the majority of evaluable patients, as well as a positive impact on reducing PSA velocity in selected patients. Furthermore, patients treated with the chimeric hTERT/LAMP vaccine demonstrated higher frequencies of hTERT-specific CD4+ T cells than those receiving the unmodified hTERT template. Additionally, the cytotoxic T lymphocytes (CTL) from these patients exhibited greater cytolytic activity against their cognate targets, suggesting that an enhanced hTERT-specific CD4+ response is capable of augmenting CTL-mediated tumor cell killing and, therefore, vaccine efficacy. Conclusions:Our demonstration of vaccine safety, successful in vivo induction of hTERT-specific immunity, and favorable impact on surrogate clinical endpoints, including PSA velocity, provides a scientific rationale for further clinical investigation of hTERT-transfected DC in the treatment of metastatic prostate cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NIH
Abstract 1959: 15-lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway
Authors: Xiangsheng Zuo, Fei Mao, Min Xu, Weiguo Xu, Rui Tian, Micheline J. Micheline J. Moussalli, Elias Elias, Haiyan S. Li, Stephanie S. Watowich, Imad Shureiqi
Journal: Cancer Research (2015)

Abstract The IL-6/STAT3 pathway is a critical signaling pathway for colitis-associated colorectal cancer (CAC). PPAR-delta (PPAR-d), a lipid nuclear receptor, upregulates IL-6. 15-Lipoxygenase-1 (15-LOX-1) is crucial to produce lipid signaling mediators to terminate inflammation. 15-LOX-1 downregulates PPAR-d. 15-LOX-1 effects on IL-6/STAT3 signaling and CAC tumorigenesis are unknown. We here report that intestinally targeted transgenic 15-LOX-1 expression in mice (15-LOX-1-Gut mice) inhibited azoxymethane and dextran sodium sulfate-induced CAC, IL-6 expression, STAT3 phosphorylation, and IL-6/STAT3 downstream target expression (Notch and MUC1). 15-LOX-1 downregulation was associated with IL-6 upregulation in human colon cancer mucosa. Re-expression of 15-LOX-1 in human colon cancer cells suppressed IL-6 mRNA expression, STAT3 phosphorylation, IL-6 promoter activity, and PPAR-d mRNA and protein expression. PPAR-d overexpression in colonic epithelial cells (PPAR-d-Gut mice) promoted CAC tumorigenesis in mice and increased IL-6 expression and STAT3 phosphorylation, whereas concomitant 15-LOX-1 expression in colonic epithelial cells (15-LOX-1-PPAR-d-Gut mice) suppressed these effects [e.g., tumor number per mouse (mean ± SE) was 4.22 ± 0.68 in wild-type littermates, 6.67 ± 0.83 in PPAR-d-Gut mice (p = 0.026), and 2.25 ± 0.25 in 15-LOX-1-PPAR-d-Gut mice (p = 0.0006)]. Identification of 15-LOX-1 suppression of PPAR-d to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides mechanistic insights that can be utilized to molecularly target CAC. Citation Format: Xiangsheng Zuo, Fei Mao, Min Xu, Weiguo Xu, Rui Tian, Micheline J. Micheline J. Moussalli, Elias Elias, Haiyan S. Li, Stephanie S. Watowich, Imad Shureiqi. 15-lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1959. doi:10.1158/1538-7445.AM2015-1959
Incidence of Kaposi sarcoma in HIV-infected patients receiving antiretroviral therapy: A prospective multicohort study from southern Africa.
Authors: J. Bohlius, F. Valeri, M. Maskew, H. Prozesky, C. Chimbetete, P. Lumano-Mulenga, T. Gsponer, M. Egger
Journal: Journal of Clinical Oncology (2011)

1589 Background: The incidence of Kaposi sarcoma (KS) is high in Southern Africa: KS is the most common cancer in HIV-infected persons. Data on KS in patients receiving antiretroviral therapy (ART) are, however, scarce in Africa. Within the framework of a large multi-cohort project, the International epidemiologic Database to Evaluate AIDS (IeDEA), we studied the incidence and risk factors for the development of KS in HIV-infected patients starting ART in Southern Africa. Methods: We analyzed prospectively collected data of HIV-infected patients who started ART with three antiretroviral drugs from at least two classes. Prevalent KS cases diagnosed before or at start of ART were excluded. Incidence rates and 95% confidence intervals (CI) were calculated based on the Poisson distribution; risk factors were estimated using crude and adjusted Cox models. Hazard ratios (HR) with 95% CI and medians with interquartile ranges (IQR) are presented. Results: 185,924 patients from 7 cohort studies in Botswana, Mozambique, South Africa, Zambia, Zimbabwe with 376,630 person-years of follow-up were included. At start of ART median age was 34 years (IQR 28–41) and median CD4 cell count 145 cells/µl (IQR 73-225). 61% of patients were female. A total of 601 incident KS cases were recorded. The incidence for KS in patients on ART was 160 (95% CI 147-173) per 100,000 person-years. The risk for KS increased with age. Adjusting for age, gender, WHO stage and CD4 cell count adults >40 years had a more than ten-fold increased risk for developing KS compared to infants (HR 11.8, 95% CI 3.0-46.2); men were more likely to develop KS compared to women (HR 1.4, 95% CI 1.1-1.7) and the risk to develop KS was increased in patients with AIDS at start ART (WHO stage IV vs. I: HR 2.2, 95% CI 1.6-3.1). Conclusions: In Southern African countries with a high prevalence of HHV-8 the risk to develop KS in HIV infected patients receiving ART increases steeply with age and is higher in patients with more advanced HIV infection.