tbuckley/cabot-search huggingface dataset:
Abstract 5253: LTβ receptor and NIK signaling activates the alternative NF-kB pathway in head and neck squamous cell carcinoma
Authors: Rita Das, Tsu-Fang Cheng, Jamie coupar, Anthony Saleh, Xingping Yang, jialing Zhang, shaleeka Cornelius, Carter Van Waes, zhong Chen
Journal: Cancer Research (2015)

Abstract Head and neck squamous cell carcinomas (HNSCC) are highly inflammatory and preferentially metastasize to lymph nodes. NF-κB, a key target and regulator of inflammatory and cancer genes is constitutively activated in HNSCC, but the upstream regulation, especially for activation of alternative pathway involving LTβ/LTβR is not clear. We hypothesized that LTβ/LTβR mediated alternative NF-kB pathway signaling is an important mechanism for activation of downstream target genes, and promotion of malignant and metastatic phenotypes in HNSCC. In this study, we have found that LTβ and LTβR are overexpressed in subsets of HNSCC (UM-SCC) tissues and cell lines. In UM-SCC cell lines, LTβ mainly activated the alternative NF-kB pathway, enhancing nuclear translocation of RELB and NF-κB2/p52, in contrast to TNFα induced activation of classical NF-κB pathway. Knockdown of LTβR by Si RNA decreased LTβR mRNA by quantitative RT-PCR and protein expression by Western blots. Knockdown of LTβR decreased its target kinase NIK, and downstream NF-κB subunits RELB and NF-κB2/p52 protein expression. Knockdown of NIK protein decreased RELB and p52 protein expression, while LTβ treatment stabilized NIK, RELB and NF-κB2/p52 expression. LTB mediated NF-κB activity was examined by transient luciferase reporter assay or using stably transfected NF-κB reporter cell line through beta lactamase Fret Blazer activity. Knockdown of LTBR and NIK functionally decreased NF-κB reporter activity, while treatment of LTB partially restored the NF-κB reporter activity. Our data have shown that constitutive and LTβ induce activation of NIK and downstream NF-κB alternate pathway proteins, RELB and NF-kB2/p52 in HNSCC. LTβ and NIK activation of the alternative NF-κB pathway may contribute to the malignant phenotype and metastasis of HNSCC. Citation Format: Rita Das, Tsu-Fang Cheng, Jamie coupar, Anthony Saleh, Xingping Yang, jialing Zhang, shaleeka Cornelius, Carter Van Waes, zhong Chen. LTβ receptor and NIK signaling activates the alternative NF-kB pathway in head and neck squamous cell carcinoma. [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 5253. doi:10.1158/1538-7445.AM2015-5253
Clinical Proof of Concept Trial of Oral Ciclopirox Olamine in Patients with Relapsed/Refractory Hematologic Malignancy
Authors: Mark D. Minden, Donna E. Hogge, Scott Weir, Jim Kasper, Lavonne Patton, Yulia Jitkova, Marcela Gronda, Rose Hurren, Lian Rajewski, Kevin Schorno, Hong Chang, Joseph M. Brandwein, Vikas Gupta, Andre C. Schuh, Suzanne Trudel, Karen W.L. Yee, Greg Reed, Aaron D Schimmer
Journal: Blood (2012)
Abstract 270: Preclinical assessment of combination therapy with selumetinib and CTLA-4 for cancer
Authors: Stefanie R. Mullins, Edmund Poon, Amanda Watkins, Paul D. Smith, Andrew Leishman, Ross Stewart, Robert Wilkinson
Journal: Cancer Research (2015)

Abstract Immune mediated therapies for Cancer (IMT-C), such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb), are showing promise in the treatment of solid tumors. However, although these treatments demonstrate clinical activity in a range of tumors, the durable benefit of these agents appears to be limited to a subset of patients. One hypothesis is that activity in these patients is limited by a lack of immune priming or by additional immunosuppressive pathways. Combination with molecular targeted therapies offers the potential to explore additional treatment strategies for patients. However, in order to select the best combination partners, a greater understanding is needed as to how each therapy affects the immune system both directly, through effects on leukocytes, and indirectly, through effects on tumor immunogenicity and the microenvironment. Selumetinib is a potent inhibitor of the mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), involved in the activation of signaling pathways which regulates cellular growth, proliferation and survival. Given that these pathways are often found aberrantly activated in human tumors, and also play key roles in the regulation of immunological processes, it is difficult to predict the combinatorial effect of MEK1/2 inhibition and IMT in cancer treatment. To assess the effect of selumetinib in a tumor model with an intact immune system, we have characterized the impact of dosing selumetinib with or without anti-CTLA-4 mAb on the immune system in the CT26 syngeneic tumor model. Flow cytometric analysis showed that this combination reduced T-cell proliferation and memory T-cell generation, but increased the frequency of splenic T cells. Selumetinib treatment decreased PD-L1 expression and increased MHC class II expression on the tumor cells, whilst decreasing myeloid-derived suppressor cell (MDSC)-like cells in the tumor. Despite the apparent ability of selumetinib to have both positive and negative effects on immune responses in vivo, the combination of selumetinib and anti-CTLA4 mAb was found to show anti-tumor activity in the CT26 colorectal tumor mouse model. These studies highlight the potential for enhancing anti-tumor immune response through combinations of molecular targeted therapies and IMT-Cs. Citation Format: Stefanie R. Mullins, Edmund Poon, Amanda Watkins, Paul D. Smith, Andrew Leishman, Ross Stewart, Robert Wilkinson. Preclinical assessment of combination therapy with selumetinib and CTLA-4 for cancer. [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 270. doi:10.1158/1538-7445.AM2015-270
PTU-005 Neurodegeneration as a prognostic factor post gastrostomy insertion: to PEG or not to PEG?: Abstract PTU-005
Authors: K E Evans, J S Leeds, H E Robson, M E McAlindon, J Grant, M Hadjivassiliou, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Gastrostomy insertion is well-accepted as a method for medium and long-term feeding. Although gastrostomy insertion in dementia is recognised as having a poor outcome there is a paucity of data pertaining to other neurodegenerative disease (examples: motor neurone disease, Parkinson9s disease and multiple sclerosis). <h3>Methods</h3> The aim of the study was to compare the mortality of patients with neurodegenerative disease undergoing gastrostomy with other subgroups requiring the procedure. Data for all patients referred for PEG insertion at our institute are prospectively included in a database. PEG referrals from February 2004 to February 2007 were analysed. Patient demographics, indications and outcome were extracted. Group 1 acute brain injury (acute stroke, head injury, subarachnoid haemorrhage), Group 2 oropharyngeal malignancy, Group 3 neurodegenerative diseases and Group 4 other/miscellaneous (cystic fibrosis, cerebral palsy, severe pneumonia, mucopolysaccharidoses, oesophageal stricture). <h3>Results</h3> 403 gastrostomies were performed (268 males, median age 64, range 18–94). Patients with neurodegenerative diseases have a worse outcome by comparison to other disease subgroups at 1 year (with a mortality of 74%, p&lt;0.002). This did not alter after adjusting for age at time of gastrostomy. <h3>Conclusion</h3> This is the first study to observe that patients with neurodegenerative disease have a higher mortality at 1 year after gastrostomy insertion than other subgroups referred. This may reflect the underlying disease. This observation has implications when discussing timing of gastrostomy and obtaining informed consent.
Multipotent Mesenchymal Stromal Cells as Graft-Versus-Host Disease Prophylaxis: a Prospective Randomised Clinical Trial
Authors: Natalia A. Petinaty, Irina N. Shipounova, Larisa A. Kuzmina, Lidya S. Lubimova, Elena N. Parovichnikova, Elena O. Gribanova, Michail M. Petrov, Nina I. Drize, Valeri G. Savchenko
Journal: Blood (2010)
Combination of lenalidomide with R-CHOP (R2CHOP) as an initial therapy for aggressive B-cell lymphomas: A phase I/II study.
Authors: G. S. Nowakowski, C. B. Reeder, B. LaPlant, T. M. Habermann, C. Rivera, W. R. Macon, D. J. Inwards, I. N. M. Micallef, P. B. Johnston, L. F. Porrata, S. M. Ansell, T. E. Witzig
Journal: Journal of Clinical Oncology (2011)

8015 Background: Lenalidomide (Len) was demonstrated to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol. 2008;26:4952-7). However, the safety and efficacy of Len in combination with standard immunochemotherapy is not known. Methods: A phase I/II study was designed to define the maximum tolerated dose and efficacy of Len administered on days 1-10 with standard R-CHOP chemotherapy (R2CHOP). Len dose escalation levels were 15 mg, 20 mg and 25 mg. All patients (pts) received 6 mg pegfilgrastim on day 2 and aspirin prophylaxis. Eligible pts were adults with newly diagnosed CD20 positive diffuse large B cell (DLBCL) or grade 3 follicular lymphoma (FL). Dose limiting toxicity (DLT) was defined as any grade 3 or higher non-hematological toxicity or a hematological toxicity resulting in a delay of the next cycle of chemotherapy. The response was evaluated using PET/CT by standard criteria (J Clin Oncol. 2007;25:579-586). Results: In the phase I portion, 3 pts received 15 mg, 3 received 20 mg and 6 received 25 mg of Len. No DLT was found and 25 mg was the recommended dose for phase II. 26 additional pts were enrolled on the 25 mg dose level in the phase II portion for a total of 32 pts at this level. The median age of these 32 pts was 64 years (19-87); 59% (19/32) were males. 28 pts (88%) had DLBCL and 4 (12%) pts had FL grade 3. International prognostic index (IPI) was low, low-intermediate, high-intermediate and high in 6, 13, 11 and 2 pts respectively. 8 pts (25%) experienced a grade 3 non-hematological toxicity and the most frequent were: febrile neutropenia (3 pts), fatigue (2 pts), thrombosis (2 pts), and dehydration (2 pts). Hematological toxicities were: grade 3 and 4 thrombocytopenia (16% and 25% of pts respectively); grade 3 and 4 neutropenia (13% and 75% of pts respectively). For 30 pts evaluable for response the overall and complete response rate was 100% and 83% respectively. Conclusions: Lenalidomide at a dose of 25 mg for days 1-10 is well tolerated when combined with standard R-CHOP21 chemotherapy. The overall and complete response rates are encouraging. Ultimately, a randomized trial will be needed to confirm the benefits of this novel combination.
Correlation of release of endothelial (progenitor) cells after chemotherapy: Kinetics with response and survival
Authors: J. M. Roodhart, M. H. Langenberg, J. S. Vermaat, M. P. Lolkema, P. O. Witteveen, E. E. Voest
Journal: Journal of Clinical Oncology (2009)

11002 Background: Recently we have shown that in preclinical models and in cancer patients certain types of chemotherapy can induce an acute release of progenitor cells (Shaked et al, Cancer Cell 2008). In the preclinical models these cells diminished the efficacy of chemotherapy. Little is known of the kinetics of circulating endothelial (progenitor) cells (CE(P)C) release after chemotherapy in humans and their respective temporal functionality. Here we investigated the temporal changes in CE(P)C release after chemotherapy. Methods: Patients with mainly advanced cancer treated with various types of MTD chemotherapy were included. Blood sampling was performed at base line, 4 hours, 7 and 21 days after start chemotherapy. The mononuclear cell fraction was analyzed for CE(P)C as previously described (Duda et al, Nature Protocols 2007) Response to chemotherapy was assessed after 3 cycles of chemotherapy following the RECIST criteria. Progression free survival (PFS) was monitored. Wilcoxon matched pairs test, Spearman correlation and the Kaplan-Meyer method were used. Results: 69 patients were included, 49 were evaluable for the complete data set. In all patients treated with paclitaxel there was an immediate increase in EPC 4 hours after start of treatment (median 246% (p&lt;0.05). Other combinations of chemotherapy induced a decrease in EPC (53%, p &lt; 0.01). These immediate changes did not correlate with response or PFS. At day 7, both CEC and EPC levels correlated with change in tumor volume after 3 cycles of chemotherapy (r 0.4, p&lt;0.05). At day 21 after start of chemotherapy, we found a consistent increase in EPC (315%, p 0.01) and CEC (291%, p 0.01) levels compared to baseline, independent of the chemotherapeutic used or of the presence of a tumor. CEC levels after 7 and 21 days correlated with PFS, regardless of the type of chemotherapy (day 7: HR 0.26 (95%CI 0.05–0.52, p &lt;0.01) and day 21: HR 0.4 (95%CI 0.1–0.9, p&lt;0.05). EPC levels did not correlate with PFS. Conclusions: These findings indicate that the longterm release of CE(P)C is a common phenomenon after treatment with chemotherapy. The correlation with a clinical response provides further support for the biological relevance of these cells.The extend of this release may influence the response to therapy and the prognosis. No significant financial relationships to disclose.
Transcatheter Mitral Valve Replacement for Patients With Symptomatic Mitral Regurgitation
Authors: David W.M. Muller, Robert Saeid Farivar, Paul Jansz, Richard Bae, Darren Walters, Andrew Clarke, Paul A. Grayburn, Robert C. Stoler, Gry Dahle, Kjell A. Rein, Marty Shaw, Gregory M. Scalia, Mayra Guerrero, Paul Pearson, Samir Kapadia, Marc Gillinov, Augusto Pichard, Paul Corso, Jeffrey Popma, Michael Chuang, Philipp Blanke, Jonathon Leipsic, Paul Sorajja, David Muller, Paul Jansz, Marty Shaw, Mark Conellan, Roberto Spina, Wesley Pedersen, Paul Sorajja, R. Saeid Farivar, Richard Bae, Benjamin Sun, Darren Walters, Andrew Clarke, Gregory Scalia, Paul Grayburn, Robert Stoler, Robert Hebeler, Gry Dahle, Kjell Arne Rein, Arnt Fiane, Maya Guerrero, Paul Pearson, Ted Feldman, Michael Salinger, Steven Smart, Samir Kapadia, Marc Gillinov, Stephanie Mick, Amar Krishnaswamy, Augusto Pichard, Paul Corso, Michael Chuang, Jeffrey Popma, Jonathon Leipsic, Philippe Blanke, John Carroll, Isaac George, Emil Missov, Andrew Kiser
Journal: Journal of the American College of Cardiology (2016)
Comparison of Hospital Mortality and Readmission Rates for Medicare Patients Treated by Male vs Female Physicians
Authors: Yusuke Tsugawa, Anupam B. Jena, Jose F. Figueroa, E. John Orav, Daniel M. Blumenthal, Ashish K. Jha
Journal: JAMA Internal Medicine (2016)

Studies have found differences in practice patterns between male and female physicians, with female physicians more likely to adhere to clinical guidelines and evidence-based practice. However, whether patient outcomes differ between male and female physicians is largely unknown.To determine whether mortality and readmission rates differ between patients treated by male or female physicians.We analyzed a 20% random sample of Medicare fee-for-service beneficiaries 65 years or older hospitalized with a medical condition and treated by general internists from January 1, 2011, to December 31, 2014. We examined the association between physician sex and 30-day mortality and readmission rates, adjusted for patient and physician characteristics and hospital fixed effects (effectively comparing female and male physicians within the same hospital). As a sensitivity analysis, we examined only physicians focusing on hospital care (hospitalists), among whom patients are plausibly quasi-randomized to physicians based on the physician's specific work schedules. We also investigated whether differences in patient outcomes varied by specific condition or by underlying severity of illness.Patients' 30-day mortality and readmission rates.A total of 1 583 028 hospitalizations were used for analyses of 30-day mortality (mean [SD] patient age, 80.2 [8.5] years; 621 412 men and 961 616 women) and 1 540 797 were used for analyses of readmission (mean [SD] patient age, 80.1 [8.5] years; 602 115 men and 938 682 women). Patients treated by female physicians had lower 30-day mortality (adjusted mortality, 11.07% vs 11.49%; adjusted risk difference, -0.43%; 95% CI, -0.57% to -0.28%; P < .001; number needed to treat to prevent 1 death, 233) and lower 30-day readmissions (adjusted readmissions, 15.02% vs 15.57%; adjusted risk difference, -0.55%; 95% CI, -0.71% to -0.39%; P < .001; number needed to treat to prevent 1 readmission, 182) than patients cared for by male physicians, after accounting for potential confounders. Our findings were unaffected when restricting analyses to patients treated by hospitalists. Differences persisted across 8 common medical conditions and across patients' severity of illness.Elderly hospitalized patients treated by female internists have lower mortality and readmissions compared with those cared for by male internists. These findings suggest that the differences in practice patterns between male and female physicians, as suggested in previous studies, may have important clinical implications for patient outcomes.
Abstract 4277: Oral administration of a traditional herbal remedy, JC001, suppresses pancreatic tumorigenesis in mice via regulating immune cell functions
Authors: Ming-Shiou Jan, Fong-Rong Hsu, You-Chain Lin, Shu-Han Chuang, Jia-Wei Lin, Meng-Hsein Chuang, Li-Jin Hsu
Journal: Cancer Research (2015)

Abstract The traditional Chinese herbal medicine JC001 is widely used as an effective liver-protecting remedy in Taiwan and China for decades. We have first examined the antitumor effects of JC001 using both mouse xenograft and oncogene-induced tumor models. Our results indicated that the numbers of M1-type macrophages, mitogen-stimulated T cell proliferation and natural killer cell activity were increased in wild-type mice with oral administration of JC001. Interestingly, continuous administration of JC001 for a month markedly reduced the numbers and the sizes of tumor nodules in a mouse pancreatic xenograft model. In contrast to this observation in immune-competent mice, our data revealed that the average tumor size in JC001-administrated nude mice was comparable with that of the control tumor-bearing nude mice without JC001 treatment, suggesting that JC001-induced antitumor activity is mediated by T cells. Adoptive transfer of the splenocytes isolated from immune-competent mice with JC001 treatment into tumor-bearing nude mice reduced tumor growth in these T cell-deficient mice. Moreover, increased cytotoxic activity of natural killer (NK) cells was also observed in mice treated with JC001. In an oncogene-induced tumor model, orally administered JC001 significantly suppressed caerulein-triggered development of pancreatic neoplasias and cancer cell metastasis in KrasG12D/w Pdx-Cre transgenic mice. Together, our results clearly suggest that JC001 exerts immunomodulatory activity mainly through regulating T and NK cell responses to suppress pancreatic cancer development and metastasis. Citation Format: Ming-Shiou Jan, Fong-Rong Hsu, You-Chain Lin, Shu-Han Chuang, Jia-Wei Lin, Meng-Hsein Chuang, Li-Jin Hsu. Oral administration of a traditional herbal remedy, JC001, suppresses pancreatic tumorigenesis in mice via regulating immune cell functions. [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 4277. doi:10.1158/1538-7445.AM2015-4277
Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: PK Guided IV Busulfan Dose Intensity Results in Improved Event Free Survival
Authors: Uday Popat, Borje S Andersson, Roland Bassett, Stefan Ciurea, Gabriela Rondon, Amin M Alousi, Paolo Anderlini, Chitra Hosing, Roy Jones, Partow Kebriaei, Yago Nieto, Issa Khouri, Elizabeth J Shpall, Srdan Verstovsek, Muzaffar Qazilbash, Marcos J de Lima, Richard Champlin
Journal: Blood (2011)
Prognostic Factors Identifiable at the Time of Onset of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.
Authors: Kyoo Hyung Lee, Seong-Jun Choi, Jung-Hee Lee, Soon-Ja Shin, Miee Seol, Young-Shin Lee, Woo-Kun Kim, Jung-Shin Lee, Je-Hwan Lee
Journal: Blood (2004)
351. Efficacious Non-Oligodendrocyte Gene Therapy Suggests a New Dogma About CNS Compartmentalization of NAA Metabolism and Supports a Metabolic Sink Theory
Authors: Dominic J. Gessler, Danning Li, Hongxia Xu, Qin Su, Reuben Matalon, Guangping Gao
Journal: Molecular Therapy (2016)

N-acetylaspartate (NAA) is the second most abundant amino acid derivative in the mammalian central nervous system (CNS). Although its physiologic function remains elusive, many CNS disorders have been associated with changes in NAA levels, e.g. Alzheimer's disease, bipolar disorder. The disease that is known to have direct connection to altered NAA metabolism is Canavan disease (CD); a leukodystrophy caused by mutations in the aspartoacylase (ASPA) gene. The current understanding is that, physiologically, the ASPA enzyme hydrolyzes NAA into L-aspartate and acetate in oligodendrocytes. Consequently, it was postulated that Canavan gene therapy has to restore ASPA expression in oligodendrocytes. However, we hypothesized that NAA can move freely and its cell-type independent break-down ameliorates Canavan disease. We constructed several tissue/cell-specific expression cassettes limiting hASPA expression to either astrocytes, neurons, oligodendrocytes, liver, heart, or muscle. We opted for the Canavan disease knock-out (CD KO) mouse model because it shows early lethality at around post-natal day 28 and the severest disease phenotype of all Canavan mouse models available. To our surprise, mice expressing hASPA restricted to peripheral organs showed extended survival and normalization of the growth curve at later time points, suggesting a contribution of peripheral organs to the disease pathomechanism. Moreover, astrocyte restricted hASPA expression produced the strongest disease recovery matching the performance of wild-type (WT) mice. Thus, our data seem to support our oligodendrocytes independent NAA metabolic sink theory. In an attempt to verify this theory, we used lower dose rAAVhASPA for localized brain injections to demonstrate that localized T2 hyperintensity signal clearance on MRI was well correlated with reduction of NAA levels by MRS. In other words, the further away from the injection site, the higher the NAA levels, which supports the idea of drainage and hydrolytic activity of NAA towards the injection side. Currently, we are investigating this metabolic sink theory in more detail by creating a functional map of therapeutic gene transfer in the brain by mass spectrometry quantification of NAA, and vector genome and ASPA transcripts analyses in different anatomic regions. Overall, our data present evidence that ASPA expression does not have to be restored in oligodendrocytes in order to rescue lethality and Canavan disease phenotype, which is in congruence with the metabolic sink theory. Furthermore, this calls into question a common hypothesis that NAA breakdown in oligodendrocytes is the mainstay for myelination and myelin defects in Canavan disease and might even support the idea that other metabolic disorders could benefit from treatment under the premise of the metabolic sink theory.