tbuckley/cabot-search huggingface dataset:
MicroRNA Profiling In Multiple Myeloma
Authors: Sophie Corthals, Su Ming Sun, Rowan Kuiper, Yvonne de Knegt, Annemiek Broyl, Bronno van der Holt, H. Berna Beverloo, Justine K Peeters, Mark van Duin, Henk M Lokhorst, Sonja Zweegman, Mojca Jongen-Lavrencic, P. Sonneveld
Journal: Blood (2010)
Immune Modulation with Pomalidomide after Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: Raúl Montiel-Esparza, Hanna A. Knaus, Joshua F. Zeidner, Ante Vulic, Gabrielle T. Prince, B. Douglas Smith, Mark J. Levis, Howard Streicher, Judith E. Karp, Leo Luznik, Ivana Gojo
Journal: Blood (2015)
Abstract CT219: Clinical and immunological analysis in a phase II trial of the glypican-3 peptide vaccine for patients with ovarian clear cell carcinoma
Authors: Shiro Suzuki, Kiyosumi Shibata, Fumitaka Kikkawa, Tetsuya Nakatsura
Journal: Cancer Research (2015)

Abstract Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) is associated with a poorer prognosis and increased chemoresistance. Therefore, new treatment modalities are urgently required for patients with OCCC refractory to chemotherapy. Glypican-3 (GPC3) is useful not only as a novel tumor marker, but also as an oncofetal antigen for immunotherapy. It is specifically overexpressed in hepatocellular carcinoma (HCC). Previous studies demonstrated that GPC3 was also overexpressed in several malignant tumors, including OCCC. We previously reported the safety of and immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced HCC. Although the efficacy of the GPC3-derived peptide vaccine against HCC patients was evaluated, other GPC3-positive cancer patients have not yet been investigated. Therefore, we conducted a phase II trial to evaluate the clinical outcome of OCCC patients treated with a GPC3-derived peptide vaccine (UMIN-CTR: 000003696). In this study, we describe the effect of vaccination with the HLA-A24 or A2-restricted GPC3 peptide on patients with OCCC. The patients were divided into three groups such as adjuvant therapy group, combined therapy group (combined to second-line chemotherapy) and recurrence or advanced group (single of vaccine treatment). The dose of GPC3 peptide injected was 3 mg per body. Patients received the intradermal injection of GPC3 peptide emulsified with incomplete Freund's adjuvant. Vaccinations were carried out biweekly from the first until the 6th and repeated at 6-week intervals after the 7th. Immunological responses were analyzed by ex vivo IFN-γ enzyme-linked immunospot assay (ELISPOT). Seventy OCCC patients were entered into clinical trial until the end of October 2014. In adjuvant group, twenty-nine of thirty-five patients have no recurrence. Recurrence pattern of all 6 patients was peritoneal metastasis. Three of twenty-nine patients with refractory OCCC achieved a significant clinical response. Ex vivo IFN-γ ELISPOT analysis in most OCCC patients revealed vaccine-induced immune reactivity against the GPC3 peptide. Our current data provide preliminary evidence of clinically meaningful benefit for GPC3 peptide vaccines in OCCC and support further evaluation of this approach in these patient populations. Citation Format: Shiro Suzuki, Kiyosumi Shibata, Fumitaka Kikkawa, Tetsuya Nakatsura. Clinical and immunological analysis in a phase II trial of the glypican-3 peptide vaccine for patients with ovarian clear 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 CT219. doi:10.1158/1538-7445.AM2015-CT219
BMP signaling activity in pediatric germ cell tumors.
Authors: N. J. Fustino, D. Rakheja, J. F. Amatruda
Journal: Journal of Clinical Oncology (2011)

9538 Background: Germ cell tumors (GCTs) arise from primitive germ cells and occur in infants, children, and adolescents. Though current treatment regimens cure many children, they also incur significant toxicity. Relatively little is known about the molecular pathogenesis of GCTs, providing a significant barrier to developing more effective, less toxic treatment regimens. Developmental signal transduction pathways have recently been implicated in the development of multiple types of cancer. We hypothesize that deregulation of TGF-β/BMP signaling underlies the pathogenesis of GCTs, and may determine their clinical behavior. Methods: We used frozen human yolk sac tumor (YST) and germinoma (GER) specimens from Children’s Medical Center. We performed real-time qPCR to evaluate expression of 86 genes involved in TGF-β/BMP signaling and compared differentiated GCTs (YSTs) to undifferentiated GCTs (GER). We performed immunohistochemistry (IHC) on a custom tissue microarray of GCT specimens. To further evaluate TGF-β and BMP signaling, we performed IHC for phospho-SMAD3 and phospho-SMAD1/5/8, respectively. We performed micro-RNA (miRNA) profiling on the same frozen tumor specimens, identified differentially regulated miRNAs among histologic subtypes, and performed web-based target prediction analysis. Results: Expression profiling of TGF-β/BMP pathway genes in YSTs and GER revealed genes distinguishing the two tumor types, including SMAD6 and SMAD7 (p<0.05). By IHC, we confirmed the absence of BMP signaling activity in undifferentiated tumors (GER), and robustly present signaling in most YSTs, a differentiated tumor type. We also observed significant intratumoral heterogeneity: a subgroup of YST showed decreased BMP gene expression and a stage I dysgerminoma showed striking upregulation of several TGF-β pathway genes. miRNA expression profiling revealed a set of differentially regulated miRNAs predicted to target the TGF-β/BMP pathway at multiple sites. Conclusions: Aberrant TGF-β/BMP signaling appears to underlie the pathogenesis and differentiation state of pediatric germ cell tumors. Gene profiling can distinguish subtypes of GCTs, with dysregulated BMP signaling being a potential target for novel developmental therapies.
The impact of platelet count (Plt#) on outcome in curable non-small cell lung cancer (NSCLC)
Authors: A. M. Safar, A. Shwaiki
Journal: Journal of Clinical Oncology (2004)

9734 Background: Proliferation of a neoplastic mass beyond ∼ 2mm requires the establishment of new blood vessels, a process termed angiogenesis, to provide oxygen and nutrients. The above applies—conceptually—both to tumor initiation and the establishment of macroscopic metastasis. Angiogenesis is thought to result from repression of antiangiogenic mediators and activation of pro-angiogenic factors, prime among them is the Vascular Endothelial Growth Factor VEGF. Platelets (Plt) contain substantial amounts of VEGF in their granules and are potential reservoirs that might facilitate tumor-promoting angiogenesis. Numerous studies support the correlation between serum levels of VEGF and inferior prognosis in multiple histologies. Because platelet lowering is readily achievable with simple pharmacologic maneuvers, it would be important to dissect the role of circulating platelets in tumor propagation mediated through angiogenesis. We hypothesized that patients with increased platelet count are at a disadvantage since this represents a milieu rich in VEGF, thus resulting in inferior curability. Methods: We retrospectively reviewed tumor registry data for stages I and II resected NSCLC. We compared the preoperative Plt# for two designated cohorts; those surviving more than 3 years (>3 yrs) vs. those succumbing in the first three years after curative resection (<3 yrs). Results: 250 patients with stage I (139 >3 years; 111 <3 years) and 52 with stage II (23 pts >3 year; 29 pts <3years) were included. As shown in the table, Plt# for the two cohorts is overlapping and indistinguishable for both stages. Conclusions: At a first approximation, correlation between Plt# and outcome does NOT appear to be present. Our results should not be taken as final. Censoring postoperative Plt# (as opposed to preoperative) and accounting for recurrence (as opposed to overall survival) are immediate considerations. No significant financial relationships to disclose.
Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury
Authors: Sachin P. Gadani, Igor Smirnov, Ashtyn T. Wiltbank, Christopher C. Overall, Jonathan Kipnis
Journal: The Journal of Experimental Medicine (2016)

The meningeal space is occupied by a diverse repertoire of immune cells. Central nervous system (CNS) injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation remains poorly understood. Here, we describe type 2 innate lymphocytes (ILC2s) as a novel cell type resident in the healthy meninges that are activated after CNS injury. ILC2s are present throughout the naive mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile. After spinal cord injury (SCI), meningeal ILC2s are activated in an IL-33–dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild-type lung-derived ILC2s into the meningeal space of IL-33R−/− animals partially improves recovery after SCI. These data characterize ILC2s as a novel meningeal cell type that responds to SCI and could lead to new therapeutic insights for neuroinflammatory conditions.
553. Comparision of AAV Serotypes for Gene Delivery to iPSC Derived RPE
Authors: Vidyullatha Vasireddy, Thu T. Duong, Jeannette L. Bennicelli, Jean Bennett
Journal: Molecular Therapy (2016)

Inherited retinal degenerations, such as retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), are characterized by progressive impairment of visual function associated with degeneration of retinal pigment epithelium (RPE) and photoreceptors. These monogenic diseases are genetically heterogeneous due to mutations in genes expressed affecting those cells. Gene therapy holds great potential for the treatment of inherited retinal diseases for which there currently is none. Efficient retinal gene transfer has been achieved with several recombinant viral vectors, including those derived from adenovirus, retrovirus, herpesvirus, and adeno-associated virus (AAV). Among these, AAV vectors appear particularly amenable to retinal gene transfer. However the success of any preclinical study depends on the availability of relevant animal models. In situations where suitable animal models are unavailable recent studies have generated proof-of concept data using personalized cell models: induced pluripotent stem cells (iPSC) derived from affected individuals and un-affected controls. With the increasing number of retinal gene therapy paradigms and recombinant vectors, in vitro bioassays characterizing vector transduction efficiency and quality are becoming increasingly important. To date, most in vitro assays using recombinant vector transduction have targeted iPSCs. To elicit additional features relevant to the disease, we differentiated iPSCs to RPE and evaluated the transduction efficiencies of a panel of AAV serotypes. Characterization of iPSC-derived RPE by qRT-PCR, immunohistochemistry, western blot analysis and flow cytometry showed the expression of typical RPE markers, phagocytic ability and gene-expression patterns similar to those of native RPE. Comparison of transduction efficiencies of different AAVs in iPSC-derived RPE was carried out using an enhanced green-fluorescent protein (eGFP) reporter gene driven by the cytomegalovirus immediate-early (CMV) promoter. At 24 to 48 hours post transduction, cells expressing GFP were identified by Typhoon scanner, and flow cytometry. Relative GFP expression was evaluated by using the software, Image-J. Of the tested AAV serotypes, AAV2 transduced iPSC-derived RPE cells most efficiently, followed by AAV7m8, AAV1 and AAV6. Differentiation into retinal neuronal cells types may require use of alternative AAV serotypes in order to obtain transduction efficiencies relevant to determination of therapeutic efficacy.
High-dose radioimmunotherapy with yttrium 90 (<sup>90</sup>Y) ibritumomab tiuxetan with high-dose etoposide (VP-16) and cyclophosphamide (CY) followed by autologous hematopoietic cell transplant (AHCT) for poor-risk or relapsed B-cell non-Hodgkin's lymphoma (NHL): Update of a phase I/II trial
Authors: A. Nademanee, S. J. Forman, A. Molina, N. Kogut, H. C. Fung, D. Yamauchi, A.-L. Anderson, D. Smith, A. N. Liu, A. Raubitschek
Journal: Journal of Clinical Oncology (2004)

6504 Background: A phase I/II trial investigated whether high-dose ibritumomab tiuxetan (Zevalin [Z]) can be safely combined with high-dose VP-16 40–60 mg/kg and CY 100 mg/kg as a conditioning regimen for AHCT. Methods: Patients undergo dosimetry study (day -21) with 5 mCi 111In-ibritumomab tiuxetan following 250 mg/m2of rituximab to confirm favorable biodistribution followed by (day -14) 40–100 mCi to deliver a target dose of 1000 cGy to highest normal organ and then VP-16 (day -4) and CY (day -2). Bone marrow biopsy is done on day-7 to estimate radiation dose and stem cells are reinfused when the radiation dose to reinfused cells is estimated to be < 5 cGy. Results: Between 5/00 and 11/03, 31 patients (17 M: 14 F), median age 51 (range, 25–59.6) with follicular (n=9), diffuse large B-cell (n=17) and mantle cell (n=5) were treated. Disease status at AHCT: 1stCR/PR=7, REL/IF = 14 and ≥2ndCR=10. Median number of prior chemo regimens was 2 (range, 1–6). All but two had received rituximab either alone (8), or in combination with chemotherapy (21). Six received VP-16 40 mg/kg while 25 received 60 mg/kg. The median dose was 70.8 mCi (range 36.6–105). The treatment was well tolerated with no transplant-related death. Mucositis, neutropenic fever and skin rash were the most common acute toxicities. All but one patient engrafted; median time to reach ANC > 500/μl and platelet > 20,000/μl was 10 days (range 8–17) and 19 days (range 12–123), respectively. There were 4 relapses at 3, 4, 12 and 24 months post AHCT. At a median follow-up of 21 months (range 1.4–43), the 2-year estimated OS and DFS is 93%(95% CI, 86–96%), and 80% (95% CI, 64–96%), respectively. Conclusion: High-dose can be safely combined with high-dose VP-16 and CY without increase in transplant-related toxicity or delay engraftment. This novel preparative regimen is well tolerated and is effective in patients with refractory B-cell NHL. Further studies and longer follow-up are required to determine the curative potential of this regimen Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen Idec, Inc. Biogen Idec, Inc. Biogen Idec, Inc. Biogen Idec, Inc.
Government’s response to inquiry on public health raises fears of more cuts
Authors: Matthew Limb
Journal: BMJ (2016)

Ministers have missed an opportunity to radically strengthen public health in England and allay MPs’ concerns about the sector, experts have said.

The government’s “disappointing” and “simplistic” response to the health select committee’s inquiry into public health has also raised fears that there could be further spending cuts.

Michael Watson, Nottingham University’s associate professor in public health, told The BMJ , “The government hasn’t even said that they will maintain public health funding, let alone increase it significantly, which is what is needed. They seem to think that public health can be done with little or no money.”

The all party health select committee, chaired by Conservative MP Sarah Wollaston, published a report on public health after 2013 in September 20161 that urged ministers to commit to protecting funding after cuts of £200 million (€235m; $245m) were made to local authorities’ budgets.

The committee …
Increased Frequency of Paroxysmal Nocturmal Hemoglobinuria Type Cells in Patients with Chronic Idiopathic Neutropenia Correlates with the Severity of the Disease and the Presence of Skewed T-Cell Expansions
Authors: Athena Damianaki, Elias Stagakis, Semeli Mastrodemou, Irene Mavroudi, Maria Velegraki, Helen Koutala, Peggy Kanellou, Charalampos Pontikoglou, Helen A. Papadaki
Journal: Blood (2015)
Abstract 3459: A new promising drug through abating endoplasmic reticulum stress response in treating endometrial cancer
Authors: Chao Wang, Wei Guo, Gordon B. Mills, Yiling Lu
Journal: Cancer Research (2015)

Abstract Background: In order to survive under ER stress conditions, cells have a self-protective mechanism against ER stress, which has been termed the ER stress response. BIP/HSPA5 is a well-known marker of ER stress. In multiple tumors, BIP expressed highly, which even confers resistance to of chemotherapeutic agents. Some methods targeting to BIP have been studied to enhance chemotherapy efficacy. CBIO showed the most relative proteins with BIP is YAP-pS127. Objects: try to understand what roles YAP plays in ER stress and to explore a new drug for endometrial cancer taking advantage of ER stress. Methods: to analyze the YAP and YAP-pS127 level as well as HSPA5 mRNA level of EC patients. Then, overexpression of YAP, proteasome inhibitors and YAP inhibitor were employed to explore the relationship between YAP and BIP by immunoprecipitate (IP), western blot (WB) and SRB techniques and to investigate the most effective combination of drugs cell. Results: 1. 322 EC patients with G3 had higher HSPA5 level and lower YAP-pS127 level compared with G1-2, patients with higher HSPA5 level had lower YAP-pS127 level. 12 EC patients had higher HSPA5 level than 12 normal women. 2. MG132 and Bortezomib induced ER stress successfully with the increase of BIP, CHOP,PERK, IRE-1a. 3. Overexpression YAP also increased the BIP, CHOP and IRE-1a level. However, Verteporfin(VP) as a YAP inhibitor decreased IRE-1a level, moreover offset the effect of MG132 on increasing IRE-1a. 4. VP induced the death of EC cells in a dose and time course manner. The sequential method of VP- Carboplatin or VP-Taxol is most effective than the simultaneous method of VP+ Carboplatin or VP+ Taxol. Conclusion: BIP impacted the grade of EC and correlated with YAP-pS127 negatively in EC. The YAP could contribute to the occurrence of ER stress. VP destroyed the capacity of ER stress response of EC cell so that it induced cell to die effectively. Making failure of ER stress response before chemotherapy will enhance the effectiveness of chemotherapeutic drugs. Citation Format: Chao Wang, Wei Guo, Gordon B. Mills, Yiling Lu. A new promising drug through abating endoplasmic reticulum stress response in treating endometrial 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 3459. doi:10.1158/1538-7445.AM2015-3459
Abstract 2456: The transmembrane domain of prostate specific membrane antigen: Deciphering the role of the Small-XXX-Small motif in oligomerization
Authors: Brianna S. Berg, Brandan M. Cook, Jack R. Hyder, James I. Godfroy, Hubert Yin, Jonel P. Saludes
Journal: Cancer Research (2015)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths among males in the United States. The prevalence of this disease and the benefits associated with early detection and treatment call for closer investigation into potential biomarkers and therapeutics targets. The high expression of the integral membrane protein called prostate specific membrane antigen (PSMA, EC 3.4.17.21) is implicated in PCa invasiveness as well as neovasculature metastasis of nonprostatic solid tumors. Little is known about the exact role of PSMA in PCa progression albeit it is one of the most validated biomarker for the diagnosis and detection of PCa. We have demonstrated that the isolated PSMA transmembrane domain (TMD) is capable of oligomerization under reducing gel electrophoresis conditions, interacting independently of extracellular domain dimerization. Following this discovery, we proceeded to determine the factor(s) responsible for its oligomerization. Since it is known that certain motifs are critical for TMD oligomerization of many transmembrane proteins, we hypothesized that the Small-XXX-Small motif in PSMA TMD may play a role in the oligomerization and subsequent activation of PSMA. Thus, to gain insight into the assembly of PSMA and the factors responsible for this assembly, we investigated if mutations at this TM motif will disrupt TM oligomerization. Our initial studies revealed that PSMA TMD has two repeat units of the Small-XXX-Small motif. This motif is known to be crucial in inducing a strong peptide self-assembly, analogous to the bitopic protein Glycophorin A. We synthesized the PSMA TMD mutant peptides using Biotage Alstra microwave peptide synthesizer, purified by high performance liquid chromatography, and characterized by MALDI-TOF mass spectrometry to establish homogeneity. SDS-PAGE gel shift assays revealed a direct correlation of oligomerization propensity and the presence of the motif, while motif knockdown led to observed loss of this property. ToxR reporter assay that qualitatively assesses relative TMD interactions revealed that oligomerization of PSMA TMD is ∼150% stronger than Glycophorin A. These findings will serve as a road map in the design of tight-binding exogenous anti-TMD peptides that target this oligomerization hot spot for possible diagnostic and therapeutic applications. Citation Format: Brianna S. Berg, Brandan M. Cook, Jack R. Hyder, James I. Godfroy, Hubert Yin, Jonel P. Saludes. The transmembrane domain of prostate specific membrane antigen: Deciphering the role of the Small-XXX-Small motif in oligomerization. [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 2456. doi:10.1158/1538-7445.AM2015-2456
PO12TENIPOSIDE-LOADED NANOPARTICLES FOR LOCAL DRUG DELIVERY IN MEDULLOBLASTOMA
Authors: Delyan P. Ivanov, Terry L. Parker, David A. Walker, Cameron Alexander, Marianne B. Ashford, Paul R. Gellert, Martin C. Garnett
Journal: Neuro-Oncology (2015)

INTRODUCTION: Current medulloblastoma (MB) therapy involving chemo-radiotherapy is moderately effective but causes severe acute haematological toxicity and serious long term neuro-toxicity affecting patients' quality of life. Delivering drugs to the post-surgical tumour bed, using drug-loaded nanoparticles (NP), offers a way of treating residual tumour with minimal systemic toxicity. Previous work demonstrated NP being taken up preferentially by tumour cells compared to the normal brain. Teniposide was chosen for NP encapsulation due to reported MB activity without neurotoxicity. METHOD: Teniposide was incorporated in Poly(ethylene glycol)-block-poly(ɛ-caprolactone) (5kDa-5kDa) NPs using solvent-emulsification and purified by gel-filtration. Drug loading was determined using UV-spectrophotometry, and drug release by dialysis and ultra-centrifugation. Comparative toxicity towards foetal brain and tumour cells was assessed in 3D in vitro MB spheroid models. Spheroid volume and metabolism dose-response curves were obtained comparing empty NP, drug-loaded NPs and free drug. RESULTS: Teniposide drug loading in the NPs was 8%w/w, but the delivery system showed rapid drug release. While the IC50 for teniposide in proliferating normal neurospheres was 20nM, the IC50 for UW228-3 tumours was 18 times higher. The drug-loaded NPs were 1.5 times less toxic to normal tissue and equally cytotoxic to tumour cells compared to the free drug. CONCLUSION: The difference in toxicity between drug-loaded NPs and free drug was not large enough to offset the drug's toxicity towards foetal cells. Nanoparticle delivery may therefore enhance the therapeutic index of drugs, but improved drug retention in the NPs will be required for confirmation.