tbuckley/cabot-search huggingface dataset:
186. Long-Term Results of pCMV-vegf165 Intramuscular Gene Transfer in Patients With Chronic Lower Limb Ischemia
Authors: Ilia Y. Bozo, Roman V. Deev, Igor L. Plaksa, Nina D. Mzhavanadze, Yuriy V. Chervyakov, Ilia N. Staroverov, Dmitriy A. Voronov, Kalinin E. Kalinin, Artur A. Isaev
Journal: Molecular Therapy (2015)

Restriction of blood flow due to atherosclerosis leads to chronic lower limb ischemia (CLI) affected 3-8% of the general population. Current pharmacological therapies have limited effects. Therefore, developing new treatments is pivotal. Gene therapy is targeted at inducing angiogenesis in ischemic extremities via increased endogenous expression of vascular growth factors. Among many, plasmid DNA vectors play a significant role in gene therapy and are safe with low immunogenicity and no risk of insertional mutagenesis. A novel drug "Neovasculgen" became the first gene therapy for patients with CLI approved by regulatory authorities in Russia in 2011. It contains a plasmid DNA encoding vascular endothelial growth factor VEGF165 (pCMV-vegf165). There was conducted a multicentre randomised controlled clinical trial of the intramuscular transfer of this new gene product in 100 patients with CLI, stage 2a-3 disease according to Fontaine. The trial lasted 6 months. It was concluded that pCMV-vegf165 transfer significantly improved pain-free walking distance (PWD) and caused no adverse effects. Efficacy and safety of this therapy were evaluated and translated into practice. Most of patients enrolled in the trial gave their consent to participate in the long-term follow-up study. The primary endpoint was PWD, the secondary – ankle-brachial index (ABI) and transcutaneous oxygen tension (TcPO2). PWD in patients who received pCMV-vegf165 increased throughout the 3-year follow-up period: by the end of the 1st year the parameter increased by 167.2% as compared to the 135.3 m baseline (p<0.05). The tendency remained positive throughout the following two years of monitoring (Fig. 1). PWD decreased by 27% within a 3-year follow-up period in control patients who received conventional therapy alone (p<0.05). Changes in secondary endpoints were less frequent and less pronounced. TcPO2 increased by 14% (10mm Hg) in the pCMV-vegf165 group by the end of the 1st year (p<0.05). The value remained stable during the next two years. TcPO2 slightly decreased in the control patients throughout the 3-year follow-up period. ABI significantly increased in the test group at each time point, but the difference comparing with control was not statistically significant. We conclude that gene therapy stably increases PWD and improves functional state of patients with CLI.
NGTS-04SUGGESTION OF TP53 GERMLINE GENETIC TESTING BASED ON RESULTS FROM NEXT GENERATION SEQUENCING OF TUMOR SPECIMEN: A CASE REPORT
Authors: Krista J. Qualmann, Dong H. Kim, Sozos Papasozomenos, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2015)

Molecular testing provides clinicians with a unique characterization of a patient's tumor. Next generation sequencing (NGS) based genetic analysis is the most commonly used tool for multiple cancer pathologies and has implications for better understanding tumorigenesis and designing potential targeted treatments. We report the case of a 52-year-old male diagnosed with anaplastic oligodendroglioma at age 50. NGS analysis of tumor specimen detected two mutations in the tumor suppressor gene TP53. Somatic TP53 mutations are frequently identified in a variety of human cancers, including primary brain tumors. Germline TP53 mutations are associated with Li-Fraumeni Syndrome (LFS), a condition in which individuals are at high risk for developing multiple primary tumors during their lifetime, typically at earlier ages of onset than the general population. Germline genetic testing is indicated when an individual's personal and/or family history raises the clinician's suspicion for the disease. Our patient's past medical history and family history were noncontributory and his presentation of disease was consistent with an isolated lesion. However, Knudson's two-hit hypothesis states that cells with pre-existing germline mutations in key genes are at high risk to become tumor cells when a somatic mutation occurs in the second allele. Therefore, the presence of two somatic TP53 mutations raised the question of whether one was also present in the germline. Subsequent germline genetic testing did detect one of the TP53 mutations, consistent with a diagnosis of LFS. This case is an example of another application of molecular tumor testing to individualize patient care. Further investigation of patients with known LFS and other hereditary cancer syndromes revealed similar molecular results in their tumor samples. While some individuals may have two somatic TP53 mutations and negative germline testing, this molecular finding may raise the clinician's awareness that further genetic work-up is warranted.
Osseointegration of titanium, titanium alloy and zirconia dental implants: current knowledge and open questions
Authors: Dieter D. Bosshardt, Vivianne Chappuis, Daniel Buser
Journal: Periodontology 2000 (2016)

Abstract Bone healing around dental implants follows the pattern and sequence of intramembraneous osteogenesis with formation of woven bone first of all followed later by formation of parallel‐fibered and lamellar bone. Bone apposition onto the implant surface starts earlier in trabecular bone than in compact bone. While the first new bone may be found on the implant surface around 1 week after installation, bone remodeling starts at between 6 and 12 weeks and continues throughout life. Bone remodeling also involves the bone–implant interface, thus transiently exposing portions of the implant surface. Surface modifications creating micro‐rough implant surfaces accelerate the osseointegration process of titanium implants, as demonstrated in numerous animal experiments. Sandblasting followed by acid‐etching may currently be regarded as the gold standard technique to create micro‐rough surfaces. Chemical surface modifications, resulting in higher hydrophilicity, further increase the speed of osseointegration of titanium and titanium‐zirconium implants in both animals and humans. Surface modifications of zirconia and alumina‐toughened zirconia implants also have an influence on the speed of osseointegration, and some implant types reach high bone‐to‐implant contact values in animals. Although often discussed independently of each other, surface characteristics, such as topography and chemistry, are virtually inseparable. Contemporary, well‐documented implant systems with micro‐rough implant surfaces, placed by properly trained and experienced clinicians, demonstrate high long‐term survival rates. Nevertheless, implant failures do occur. A low percentage of implants are diagnosed with peri‐implantitis after 10 years in function. In addition, a low number of implants seem to be lost for primarily reasons other than biofilm‐induced infection. Patient factors, such as medications interfering with the immune system and bone cells, may be an element contributing to continuous bone loss and should therefore be monitored and studied in greater detail.
CPX-351: A Randomized Phase 2b Study of CPX-351 v. Intensive Salvage Therapy in '65 Yo First Relapse AML Patients: Initial Efficacy and Safety Report
Authors: Jorge E. Cortes, Eric J Feldman, Stuart L. Goldberg, David A. Rizzieri, Kim H. Paulsen, Arthur C. Louie, Jonathan E. Kolitz
Journal: Blood (2011)
OC-085 Nutritional intervention in patients undergoing colorectal surgery: support for the routine prescription of oral nutritional supplements pre- and post-operatively
Authors: P G Lidder, S Thomas, S C Fleming, K B Hosie, S J Lewis
Journal: Gut (2010)

<h3>Introduction</h3> There is good evidence that nutritional support is beneficial. The advent of minimal access surgery allied with enhanced recovery pathways allows us to successfully feed patients earlier than ever before. With data suggesting early feeding is preferential to “nil by mouth” in terms of morbidity and hospital length of stay, we set out to determine the most important periods in which to provide nutritional support by assessing the temporal relationship between nutrition provision and surgery. Furthermore, based on the extensive works of Lungqvist, we assessed impact of feeding against physiological endpoints such as glucose homeostasis as well as more conventional clinical endpoints. <h3>Methods</h3> Prospective four-armed double-blind randomised control trial. Patients allocated to one of four nutritional interventions: control pre-op/control post-op, active pre-op/control post-op, active pre-op/active post-op and control pre-op/active post-op. Patients were either given pre-op® or placebo pre-operatively, or fortifresh® or placebo postoperatively according to allocation. Caloric intake was assessed pre-operatively and during the early postoperative period. Endpoints included, glucose homeostasis, insulin resistance, biochemical markers of inflammation and morbidity/mortality data. <h3>Results</h3> 120 patients were recruited. Demographically, groups were well matched. 94% of patients reported weight loss in the 3 months prior to surgery, of which 55% reported weight loss &gt;5% of their normal body weight. Glucose homeostasis was better in supplemented groups (p=0.004), and there were reductions in insulin resistance (p=0.001) compared with standard care (placebo/placebo). Muscle strength (p&lt;0.001) and lung function (p=0.035) were similarly improved following surgery. There were no significant differences in immediate post-operative complications but at 30 days the group receiving pre- and post-operative supplements developed fewer complications than those receiving standard care (placebo/placebo) (p=0.003, χ<sup>2</sup>=8.695). <h3>Conclusion</h3> Disease-related malnutrition is prevalent within patients suffering from colorectal cancer. Nutritional intake in the peri-operative period remains inadequate and poor nutritional intake should be corrected with oral nutritional supplements as even modest intake results in improved biochemical response to stress and reductions in morbidity.
Prolonged Ex Vivo Expansion (7–10 Days) of Cord Blood (CB) Recryopreserved and Rethawed Aliquots with Anti-CD3, IL-2, IL-12 Significantly Expands NKT Cells, NKT KIR Substes and NK Cytotoxicity Compared to Short-Term Expansion: Potential for CB Adoptive Cellular Immunotherapy (ACI).
Authors: Janet Ayello, Prakash Satwani, Carmella van de Ven, Elizabeth Roman, Allison O’Neill, Max Shutran, Matthew Greenhawt, Laxmi Baxi, Lynn Simpson, Joanne Kurtzberg, Mitchell S. Cairo
Journal: Blood (2004)
Assessment of burden of illness in women with HER2+ metastatic breast cancer: Findings from a community web-based survey.
Authors: M. Mayer, J. F. Doan, K. Lang, S. A. Hurvitz, D. Lalla, R. M. Woodward, M. Brammer, J. Menzin, D. Tripathy
Journal: Journal of Clinical Oncology (2011)

e11121 Background: To better understand burden of illness in women with HER2+ metastatic breast cancer (MBC), we conducted a survey to evaluate their treatment experiences. Methods: This one-time, web-based survey was conducted with the help of 4 independent U.S. breast cancer support groups. Respondents were invited to participate via email, and were required to be female, aged 18+ with HER2+ MBC, and to have received active treatment in the past month. Approximately 100 demographic, clinical, employment, quality of life, social and resource use data items were collected. Results: 130 women with HER2+ MBC completed the survey. The majority of respondents were 45-59 years old (54.6%), white (93.9%), living with a spouse or partner (72.3%) and had at least a college education (70.8%). The most common comorbid conditions were high blood pressure (10.0%), thyroid disease (4.6%), diabetes without complications (4.6%), congestive heart failure (3.9%) and rheumatologic conditions (3.9%). While over 65% were full time employed at the time of MBC diagnosis, only 26% were at the time they completed the survey. 69% were currently taking a trastuzumab containing regimen, commonly with another medication. Frequently used medications included lapatinib and paclitaxel. Symptoms reported as frequently bothersome by at least 20% of women were: tiredness (52%), decreased sexual interest (50%), difficulty sleeping (39%), worry (39%), joint/ muscle pain (34%), difficulty concentrating (27%), alopecia (24%), low back pain (23%), depressed mood (22%), constipation (20%), and tingling of hands or feet (20%). Despite their disease, these women expressed high levels of satisfaction with their lives and relationships (with family, friends, and other women with MBC), but were less satisfied with their employment and their feeling about the future. They expressed higher levels of burden due to pain/discomfort and anxiety/depression than due to usual activities, self-care, and mobility. Fewer than 10% had discussed palliative care options with their doctor. Conclusions: This community survey of women with HER2+ MBC provides valuable insights into their demographics, work status, treatment, and symptom burden.
Normalization of FDG-PET Pre-ASCT with Additional Non-Cross Resistant Chemotherapy Improves EFS in Patients with Relapsed and Primary Refractory Hodgkin Lymphoma-Memorial Sloan Kettering Protocol 04-047
Authors: Craig H. Moskowitz, Stephen D. Nimer, Andrew D. Zelenetz, Paul A. Hamlin, Steven M. Horwitz, Ariela Noy, Carol S. Portlock, David J. Straus, John Gerecitano, Tarun Kewalramani, Jill M. Vanak, Jocelyn C. Maragulia, Joachim Yahalom
Journal: Blood (2008)
Multi-Targeted Receptor Tyrosine Kinase Inhibitor, ABT-869, Induces Apoptosis and Inhibition of Proliferation of Ba/F3 FLT-3 ITD Mutant Cells.
Authors: Jenny E. Hernandez, Junling Li, Ru-Qi Wei, Paul Tapang, Steven K. Davidsen, Daniel H. Albert, Patrick A. Marcotte, Keith B. Glaser, Cecilia Fu, Kathleen M. Sakamoto
Journal: Blood (2007)
Expression of topoisomerase (topo) II in adult acute myeloid leukemia (AML): Relationships to immunophenotype and treatment outcomes.
Authors: A. P. Michelson, K. J. Kopecky, E. R. Koegle, J. E. Anderson, J. E. Godwin, S. H. Petersdorf, A. F. List, C. L. Willman, F. R. Appelbaum, J. P. Radich, M. K. Ganapathi, R. N. Ganapathi, A. Advani
Journal: Journal of Clinical Oncology (2011)

6564 Background: Anthracyclines used in the treatment of AML target topo II. Topo II α and β are genetically distinct with different expression (expr) patterns and cellular distribution. While topo IIα has been associated with increased proliferation and an adverse prognosis in AML, there is no information regarding topo IIβ. This study examined the relationships of topo IIα and β expr to immunophenotype (IP), multidrug resistant (MDR) phenotype and outcomes in adult AML. Methods: 230 pts with non-M3 AML by FAB criteria who received frontline ara‐C/daunomycin (AD) therapy during the years 1992-98 on studies SWOG-9031, ‐9126, ‐9333 or ‐9500 were included (median age 63 years [18-88], WBC 29x109/L [0.8-274]). RT-PCR of RNA from marrow blasts was run with topo IIα and β specific primers (ABI PRISM 7900HT). Topo IIα and β expr in pts, normalized to internal standard β2‐microglobulin, was measured by log (fold-change) relative to the Kasumi AML cell line. Treatment outcomes - complete response (CR), resistant disease (RD), and relapse-free and overall survival (RFS, OS) - were analyzed by logistic or Cox regression. Results: Topo IIα and β data were available for 211 pts. Topo IIα expr in pts ranged from 298-fold less to 91-fold more than in the Kasumi AML cell line, but was not significantly correlated with any pt characteristic, IP or treatment outcome in uni- or multivariate analysis. In contrast, topo IIβ ranged from only 9‐fold less to 10-fold more than the cell line, but was associated with higher blast percentage in marrow (P=0.0001) or blood (P=0.0055); higher CD7 (P=0.0071); and lower CD14 (P<0.0001) and CD54 (P<0.0001) in multivariate regression analysis. In 105 pts with MDR data, topo IIβ was also inversely correlated with Rhodamine efflux (P<0.0001) and CD11c (P=0.0010). However after adjusting for prognostic factors, topo IIβ was not significantly related to any outcome, nor did topo IIβ interact significantly with any prognostic factors. Conclusions: Topo IIβ expr reflects aspects of disease biology, such as highly proliferative disease (higher blasts), IP and MDR, and thus may not be an independent variable influencing outcome in adult AML pts treated with anthracycline-based therapy.
Abstract 697: c-MET as a potential target in ovarian clear-cell carcinoma
Authors: Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Yoo Young Lee
Journal: Cancer Research (2015)

Abstract Purpose: Recent reports revealed that c-MET activation is associated with epithelial ovarian carcinoma (EOC) and is association with poor prognosis. In this study, we investigated the effects of therapeutic targeting for c-MET in ovarian clear cell carcinoma (OCCC). Experimental Design: Expression levels of c-MET in the epithelial ovarian carcinomas and normal ovarian tissues were evaluated using real-time PCR. To test c-MET inhibitors in CCC cell lines, we performed in vitro experiments including MTT and apoptosis assay. We performed Western blots to evaluate the c-MET expression and down-stream pathway. In addition, we performed in vivo therapy experiments in orthotopic ovarian cancer mice model (RMG1) and patient-derived tumor xenograft (PDX) models of CCC to confirm these effects. Results: The c-MET expression was significantly increased in CCCs compared with serous carcinomas and normal ovarian tissues (P &amp;lt; 0.05). CCC cells treated with c-MET inhibitors (SU11274 or crizotinib) demonstrated significantly decreased cell viability and increased apoptosis. Western blot assay showed that the protein expressions for c-MET signaling pathway were decreased by c-MET inhibitor. Moreover, tumor weight was significant decreased in both in vivo RMG1 and PDX models receiving SU11274 treatment compared with control (P &amp;lt; 0.05). Conclusion: These results show that c-MET inhibitor has the significant anti-tumor effects in ovarian CCC, and suggested that c-MET could have the potential agent in the therapy for this cancer. Citation Format: Jeong-Won Lee, Byoung-Gie Kim, Duk-Soo Bae, Yoo Young Lee. c-MET as a potential target in 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 697. doi:10.1158/1538-7445.AM2015-697
COPD+OSA: can two bad things be good for you?
Authors: Franco Laghi, Robert L Owens
Journal: Thorax (2016)

COPD and obstructive sleep apnoea (OSA), two highly prevalent disorders,1 are both associated with substantial sleep-related hypoventilation.2 Sleep-related hypoventilation in these patients is of greater magnitude than that recorded in healthy subjects. These observations raise the possibility that patients concurrently affected by COPD and OSA, also known as overlap syndrome, may develop worse sleep-related hypoventilation than patients with COPD or OSA alone. When sufficiently severe, sleep-related hypoventilation can reset the chemoreceptor threshold with resultant daytime hypercapnia.3 This (hypothetical) chain of events could explain why, despite less severe airway obstruction, the prevalence of daytime hypercapnia in patients with overlap syndrome is greater than that in patients with COPD4 or OSA alone.5 More profound hypercapnia and nocturnal hypoxaemia might also explain the reported increase in mortality in overlap syndrome compared with COPD.6

He et al 7 advance our understanding of the mechanisms of sleep-related hypoventilation in overlap syndrome. Specifically, and for the first time, the investigators compare the neural respiratory drive and ventilation during non-rapid eye movement (NREM) sleep in overlap syndrome against drive and ventilation in COPD alone, OSA alone and in healthy subjects. Neural respiratory drive was quantified as the amplitude of the diaphragm electromyogram signal (EMGdi) recorded with oesophageal electrodes.8 To assess upper airway resistance, the investigators computed the ratio of tidal volume to EMGdi.9

As expected, minute ventilation during sleep decreased in all participants: 10% in healthy subjects, 24% in COPD, 21% in OSA and ‘only’ 27% in patients with overlap syndrome. This lack of synergy between COPD and OSA in worsening sleep hypoventilation resulted from the unique response …
714. Gene Therapy Rescues Cone Function and Viability in an Rp2 Knockout Mouse Model for X-Linked Retinitis Pigmentosa Over a Wide Dose Range and a Broad Therapeutic Time Window
Authors: Suddhasil Mookherjee, Suja Hiriyanna, Kayleigh Kaneshiro, Haohua Qian, Tiansen Li, Hemant Khanna, Peter Colosi, Anand Swaroop, Zhijian Wu
Journal: Molecular Therapy (2015)

Retinitis pigmentosa (RP) refers to a diverse group of inherited retinal dystrophies characterized by a progressive loss of photoreceptors, resulting in vision impairment or blindness. The prevalence of the disease is 1 in 3,500 to 4,000 worldwide. X-linked RP (XLRP) accounts for ~15% of all RP cases and is one of the most severe forms of retinal degeneration. About 10% of the total XLRP cases are caused by mutations in the RP2 gene. A recently developed Rp2 knockout (Rp2-KO) mouse model exhibits early onset, progressive cone photoreceptor dysfunction and degeneration, mimicking early cone involvement in patients with RP2 mutations. To develop gene therapy for the disease, we generated and characterized a self-complementary AAV8 vector carrying the human RP2 expression cassette (AAV8-scRK-RP2), and examined its efficacy in the Rp2-KO mice. Our initial results demonstrated successful cone function rescue following subretinal administration of the vector to the mice (ASGCT 2014, poster#122). In the present study, we continued to examine the long term safety and efficacy of the vector using a broader dose range. Four to six week-old Rp2-KO mice received unilateral subretinal injections of the vector with doses ranging from 5×107 to 1×109 vector genomes (vg)/eye. The fellow eyes were injected with vehicle as controls. Retinal function was assessed by electroretinography (ERG) and optomotor test up to 18 months of age. Our results revealed significantly higher amplitude and faster recovery of cone ERG in vector-treated eyes than control eyes in almost all dose groups through the duration of monitoring starting from 4 months of age. In addition, remarkably better visual acuity was observed in the vector-treated eyes at 18 months of age. The treatment also reversed M-opsin mis-localization, restored cone PDE expression and maintained cone viability. Interestingly, this rescue was achieved in the Rp2-KO mice even when treated at 10-month of age, suggesting the potential benefit of the treatment to older patients. Retinal toxicity was only observed in mice receiving the highest vector dose (1×109 vg/eye), as reflected by reduced rod ERG amplitude and thinner photoreceptor layer. We conclude that our RP2 AAV vector can rescue cone function and viability over a wide dose range and a broad therapeutic time window, which paves the way for future clinical studies.
Inhibition/Depletion of CD26/DPPIV Enhances Survival Promoting Activity of SDF-1/CXCL12 and Myelosuppressive Activities of Inhibitory Chemokines on Hematopoietic Progenitor Cells.
Authors: Hal E. Broxmeyer, Timothy B. Campbell, Scott Cooper, Giao Hangoc
Journal: Blood (2007)