tbuckley/cabot-search huggingface dataset:
599. Deep Informatics Utilized to Design MiniPromoters for Driving PAX6-Like Retinal Expression with AAV
Authors: Jack W. Hickmott, Chih-yu Chen, David J. Arenillas, Yifeng Li, Laurie L. Molday, Andrea J. Korecki, Siu Ling Lam, Siu Ling Lam, Russell J. Bonaguro, Michelle Zhou, Alice Y. Chan, Sanford L. Boye, William W. Hauswirth, Robert S. Molday, Wyeth W. Wasserman, Elizabeth M. Simpson
Journal: Molecular Therapy (2015)

Purpose: Gene-based therapies are making a comeback, as evidenced by the clinical success of Glybera, rAAV2. RPE65, and rAAV2. REP1. These therapies utilize ubiquitous promoters, however future gene therapies may benefit from promoters that can direct tissue- and cell-type specific expression. Capturing the expression of a human gene in a promoter small enough to use in AAV is challenging. Paired box six (PAX6) encodes a transcription factor with a complex and potentially therapeutically-useful retinal-expression pattern. Also, PAX6 has several previously published discrete regulatory regions (RRs), and therefore may contain modular regulation suitable for MiniPromoter design. Finally, mutations in PAX6 cause the vision-loss disorder aniridia, and a MiniPromoter capable of recapitulating the expression of PAX6 would be a useful tool for an aniridia gene therapy. Methods: PAX6 RRs were predicted using Hi-C, UCSC Genes, CAGE, 100 vertebrate phastCons, transcription factor binding site (TFBS), Segway and ChromHMM data. MiniPromoters were cloned into AAV genomes containing an emGFP reporter and WPRE, packaged into AAV2(Y272F, Y444F, Y500F, Y730F, T491V), and administered to postnatal day 14 mice by intravitreal injection. Ocular tissue was collected 30 days after injection, emGFP expression was evaluated by epifluorescent imaging of mouse retinas, and staining with antibodies against PAX6, Brn3a, syntaxin, and calbindin. MiniPromoters driving PAX6-like expression were examined for unique TFBSs using oPOSSUM 3. Results: A PAX6 containing highly interactive domain was revealed within which most previously published PAX6 RRs are located. Within this domain, 31 RRs were bioinformatically predicted, nine of which were selected to construct seven MiniPromoters. Of these MiniPromoters, two did not drive interesting emGFP expression in the retina, and five drove expression in the two retinal layers that express PAX6 (ganglion cell and inner nuclear). Twenty-one TFBSs were found to be unique to these MiniPromoters. Interestingly, one of the five (Ple255) not only drives expression in the same cell layers that express PAX6, but also in all the same cell types (ganglion, amacrine, and horizontal). Conclusions: Bioinformatic approaches can be used to design MiniPromoters capturing the endogenous expression pattern of a gene for a specific tissue. The resulting MiniPromoters may be important tools for future retinal gene therapy, with Ple255 being especially applicable to gene therapy for aniridia.
Analysis of an observational registry of gastrointestinal stromal tumor (GIST) patients (pts) in the United States: reGISTry
Authors: P. W. Pisters, J. C. Trent, C. D. Blanke, J. Picus, E. Stealey, K. McDougall, M. von Mehren
Journal: Journal of Clinical Oncology (2009)

10557 Background: This observational reGISTry, initiated 11/04, characterizes the evolving patterns of care for GIST, such as the recent use and approval of Imatinib mesylate (IM) in adjuvant GIST. Methods: Data from consented pts (e.g. demographics, clinical characteristics, therapy, outcomes) are entered onto a web-based database. Updated analyses are performed every 6 months (mo), with data from unique sites being compared to the aggregate. Results: 792 pts enrolled from 121 centers, 55% from community practices. 79% were diagnosed with localized tumor, 87% of which received surgery as primary treatment. 94% had c-kit testing and 4% had mutational analysis performed at any time (1.4% of the pts in the community; 7.8% in Universities). 59% of pts had mutations in KIT Exon 11, 12% in Exon 9, 3% in Exon 17, 9% in PDGFRA Exon 18 and 18% had no detectable mutations. 13% of pts from Universities were enrolled in clinical trials vs 3% in the community. 78% of pts receiving IM at any time started at 400mg qd and 70% of pts receiving Sunitinib malate (SU) started at 50mg (4 wks on, 2 wks off). 6.6% of all pts received neoadjuvant IM, for a median of 4.3 mo for those pts that have completed (81%). 120 pts (15%) received adjuvant IM (13% of the pts in the community; 17% in Universities). Prior to Jun07 (ACOSOG Z9001 adjuvant IM positive results released) 14% of eligible pts received adjuvant IM vs 29% after Jun07. Median duration of adjuvant IM was 361 days for those pts that have completed (43%). Conclusions: reGISTry is a useful tool for measuring evolving pt management patterns in GIST capturing treatment variations from standard guidelines and differentiating management in Universities from that occurring in the community. Mutational analysis and clinical trial participation are still infrequent. The starting dose of IM and SU remains 400mg and 50mg, respectively, for most pts. The use of adjuvant IM has increased after Jun 07, suggesting that prescribing habits may have been influenced by evolving study data in these pts. [Table: see text] [Table: see text]
HCD122, an Antagonist Human Anti-CD40 Monoclonal Antibody, Inhibits Tumor Growth in Xenograft Models of Human Diffuse Large B-Cell Lymphoma, a Subset of Non-Hodgkins Lymphoma.
Authors: Ssucheng J. Hsu, Lin A. Esposito, Sharon L. Aukerman, Seema Kantak, Amer M. Mirza
Journal: Blood (2006)
The Effect of Rituximab in Combination with MEVP Chemotherapy and rhG-CSF in Old Patients of Refractory and Terminal Non-Hodgkin’s Lymphoma.
Authors: Meihua Qian, Wensong Wang, Jianping Lan, Lianming Wang, Shumei Zhan, Zhonsen Zhao, Wenjian Xu
Journal: Blood (2006)
MASS TREATMENT OF HOOKWORM INFECTION
Authors: K S Mhaskar
Journal: JAMA (1922)

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Primary Care Physician Volume and Quality of Diabetes Care
Authors: Andrew Cheung, Thérèse A. Stukel, David A. Alter, Richard H. Glazier, Vicki Ling, Xuesong Wang, Baiju R. Shah
Journal: Annals of Internal Medicine (2016)

Background: A relationship between higher patient volume and both better quality of care and better outcomes has been shown for many acute care conditions. Whether a volume–quality relationship exists for the outpatient management of chronic diseases is uncertain. Objective: To explore the association between primary care physician volume and quality of diabetes care. Design: Cohort study. Setting: The study was conducted using linked population-based health care administrative data in Ontario, Canada. Patients: 1 018 647 adults with diabetes in 2011 who received care from 9014 primary care physicians. Two measures of volume were ascertained for each physician: overall ambulatory volume (representing time available to devote to chronic disease management during patient encounters) and diabetes-specific volume (representing disease-specific expertise). Measurements: Quality of care was measured over a 2-year period using 6 indicators: disease monitoring (eye examination, hemoglobin A1c testing, and low-density lipoprotein cholesterol testing), prescribing appropriate medications (angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers and statins), and adverse clinical outcomes (emergency department visits for hypoglycemia or hyperglycemia). Results: Higher overall ambulatory volume was associated with lower rates of appropriate disease monitoring and medication prescription. In contrast, higher diabetes-specific volume was associated with better quality of care across all 6 indicators. Limitation: Only a select set of quality indicators and potential confounders could be ascertained from available data. Conclusion: Primary care physicians with busier ambulatory patient practices delivered lower-quality diabetes care, but those with greater diabetes-specific experience delivered higher-quality care. These findings show that relationships between physician volume and quality can be extended from acute care to outpatient chronic disease care. Health policies or programs to support physicians with a low volume of patients with diabetes may improve care. Primary Funding Source: Canadian Institutes of Health Research.
Time to First Progression, but Not Β2-Microglobulin, Predicts Outcome in Myeloma Patients Who Received Thalidomide as Salvage Therapy.
Authors: Antonio Palumbo, Sara Bringhen, Patrizia Falco, Cecilia Rus, Federica Cavallo, Maria Teresa Ambrosini, Ilaria Avonto, Francesca Gay, Gabriele Gallone, Tommaso Caravita, Benedetto Bruno, Mario Boccadoro
Journal: Blood (2006)
Antitumor Activity and Mechanism of Action of a Novel Stat3 Inhibitor, WP1066, Against Human B-Cell Non-Hodgkin’s Lymphoma and Multiple Myeloma.
Authors: Ling-Yuan Kong, Vaibhav Kapuria, Geoffrey Bartholomeusz, Moshe Talpaz, Waldemar Priebe, Nicholas J. Donato
Journal: Blood (2005)
Prior Therapy with DNA Methyltransferase Inhibitors (DNMTI) Predicts for Lower Remission Rates and Worse Survival In Secondary Acute Myeloid Leukemia Patients (sAML) Receiving Remission Induction Therapy
Authors: Sanjay R. Mohan, Alex Fu, Ramon V. Tiu, Edward Copelan, Yogen Saunthararajah, Anjali Advani, Ronald Sobecks, Manual Afable, Ricki Englehaupt, Katarina Paulic, Marc Earl, Matt Kalaycio, Jaroslaw P Maciejewski, Mikkael A. Sekeres
Journal: Blood (2010)
Elevated Absolute Lymphocyte Counts Following Acute Graft Vs. Host Disease Treatment Is Associated with Therapeutic Responses and Lower Non-Relapse Mortality Following Umbilical Cord Blood Transplant,
Authors: Michael R Verneris, Sanyukta Janardan, Michael J Burke, Todd E. Defor, Claudio Brunstein, Bruce R. Blazar, Jeffrey S. Miller, John E. Wagner, Daniel Weisdorf, Margaret L. MacMillan
Journal: Blood (2011)
Efficacy of the CryoBalloon Focal Ablation System for the eradication of dysplastic Barrett’s esophagus islands
Authors: Hannah Künzli, Dirk Schölvinck, Sybren Meijer, Kees Seldenrijk, Jacques Bergman, Bas Weusten
Journal: Endoscopy (2016)

Background and study aim Cryoablation can be used for the treatment of Barrett's esophagus (BE). A recent dosimetry study, using the CryoBalloon Focal Ablation System (CryoBalloon), demonstrated that 10-second ablations result in complete eradication of BE. However, the efficacy of 10-second ablation in a larger cohort of patients has not been investigated, nor has the potential of precise targeting of specific areas. The aim of the study was to assess the efficacy and performance (i. e. targeting of BE islands) of a 10-second cryoablation using the CryoBalloon. Results A total of 30 patients were enrolled (worst pathology: low grade dysplasia in 14 [47 %], high grade dysplasia in 7 [23 %], early adenocarcinoma in 9 [30 %]). Of the 47 BE islands, 44 (94 %) were adequately targeted. Complete eradication of intestinal metaplasia and dysplasia was observed in 100 % of the completely ablated areas. No stenoses were observed. Conclusion Cryoablation of BE islands using the CryoBalloon is effective. BE islands were effectively targeted.
A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease
Authors: Dimitri Tchernitchko, Quentin Tavernier, Jérôme Lamoril, Caroline Schmitt, Neila Talbi, Said Lyoumi, Anne-Marie Robreau, Zoubida Karim, Laurent Gouya, Eric Thervet, Alexandre Karras, Hervé Puy, Nicolas Pallet
Journal: Journal of the American Society of Nephrology (2016)

CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP, δ -aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA. We tested the hypothesis that PEPT2 genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for PEPT2 . At last follow-up, carriers of the PEPT2*1*1 genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants PEPT2*1/*2 and PEPT2*2/*2 (mean±SD eGFR: 54.4±19.1, 66.6±23.8, and 78.1±19.9 ml/min per 1.73 m 2 , respectively). Change in eGFR (mean±SD) over the 10-year period was −11.0±3.3, −2.4±1.9, and 3.4±2.6 ml/min per 1.73 m 2 for PEPT2*1/*1 , PEPT2*1*2 , and PEPT*2*2*2 carriers, respectively. At the end of follow-up, 68% of PEPT2*1*1 carriers had an eGFR&lt;60 ml/min per 1.73 m 2 , compared with 37% of PEPT2*1*2 carriers and 15% of PEPT2*2*2 carriers. Multiple regression models including all confounders indicated that the PEPT2*1*1 genotype independently associated with an eGFR&lt;60 ml/min per 1.73 m 2 (odds ratio, 6.85; 95% confidence interval, 1.34 to 46.20) and an annual decrease in eGFR of &gt;1 ml/min per 1.73 m 2 (odds ratio, 3.64; 95% confidence interval, 1.37 to 9.91). Thus, a gene variant is predictive of the severity of a chronic complication of AIP. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation.
Phase 1 multicenter, open-label study to establish the maximum tolerated dose (MTD) of two administration schedules of E7389 (eribulin) liposomal formulation in patients (pts) with solid tumors.
Authors: Ishtiaq Husain Zubairi, Emma Jane Dean, L Rhoda Molife, Juanita Suzanne Lopez, Malcolm Ranson, Fatima El-Khouly, Claudio Isaac Savulsky, Larisa Reyderman, Yan Jia, Emily Hutton, Rosemary Morrison, Lorna Sweeting, Alastair Greystoke, Jorge Barriuso, Rebecca Sophie Kristeleit, T.R. Jeffry Evans
Journal: Journal of Clinical Oncology (2016)

2524 Background: Eribulin, a microtubule dynamics inhibitor, is approved in the US for the treatment of pts with metastatic breast cancer who have previously received ≥ 2 chemotherapeutic regimens for metastatic disease including an anthracycline and a taxane in the adjuvant/metastatic setting. Preclinical evidence suggested improved efficacy and lower toxicity with a liposomal formulation of eribulin (eribulin-LF). The primary objective of this study was to determine the MTD and dosing schedule for eribulin-LF. Secondary objectives included determining safety, pharmacokinetics (PK), and efficacy. Methods: Using a conventional 3 + 3 study design, eligible pts received escalating doses (1.0 to 3.5 mg/m2) of eribulin-LF (60-min, i.v. infusion) on day (D) 1 of a 21-day cycle (schedule [S] 1) or on D1 and D15 of a 28-day cycle (S2). An expansion phase confirmed the safety of eribulin-LF in pts with endometrial, ovarian, or HER2-negative breast cancer. Results: Of 58 pts (S1: n = 20; S2: n = 38): 65% were female, median age was 62 yrs (range 33–75), 65% had an ECOG PS of 1, and 10 pts had metastatic breast cancer. Dose-limiting toxicities were: S1, grade (G) 4 hypophosphatemia (n = 1), G4 increased ALT/AST (n = 1), both at eribulin-LF 1.5 mg/m2; S2, G4 febrile neutropenia (n = 1; 1.5 mg/m2); G3 increased ALT/AST (n = 1), and G4 neutropenia (n = 1), both at 2 mg/m2. MTD was 1.4 mg/m2 in S1 and 1.5 mg/m2in S2; the latter dose and schedule were used in the expansion phase (n = 23). Treatment-emergent adverse events (TEAEs) included peripheral neuropathy (S1: 35%, S2: 8%) and neutropenia (S1: 20%, S2: 34%). TEAEs of G3 or higher occurred in 55% (S1) and 39% (S2). Eribulin-LF exhibited single-phase PK, and was quantifiable ~18 days postdose. Exposure was dose-dependent and t1/2 was ~35 hrs. Promising clinical activity was observed in pts with breast cancer (5/10 partial responses, 3/10 stable disease). Conclusions: In this phase 1 study, eribulin-LF was well tolerated, with promising activity in patients with breast cancer. Eisai Inc. Clinical trial information: NCT01945710.
Abstract 4554: An evaluation of the role of Mucin in drug resistant ovarian cancer
Authors: Steven M. Richards, Robert B. Campbell
Journal: Cancer Research (2015)

Abstract MUC1 is a transmembrane glycoprotein that is overexpressed in epithelial ovarian cancer. Due to extensive O-glycosylation, mucins form a physical barrier that limits the intracellular accumulation and cytotoxic effect of chemotherapeutic drugs. Our investigation represents a key step in determining if drug resistance in ovarian cancer develops due to altered MUC1 expression and glycosylation. Immunoblotting and ELISA techniques were utilized to characterize the extent of membrane-bound and shed MUC1 expression in drug-resistant and drug-sensitive ovarian cancer cells. An (anti-MUC1) antibody-based in vitro model was employed to determine if the inhibition of O-glycosylation enhanced functional access of small molecule drugs using FACS and fluorescence microscopic analyses. Expression of MUC1 was detected in both the drug resistant ovarian cancer cell line SK-OV-3 (MDR) and the parent cell line SK-OV-3 (WT), with the highest levels observed in the drug resistant sub-clone. The greatest improvement in functional anti-MUC1 antibody access following inhibition of O-glycosylation was observed in the drug-resistant ovarian cancer cells. Our results provide evidence to support drug resistance in ovarian cancer due in part to a mucin barrier mesh. The inhibition of mucin O-glycosylation may be a viable strategy to improve drug delivery and efficacy of small molecule delivery to ovarian carcinomas. Citation Format: Steven M. Richards, Robert B. Campbell. An evaluation of the role of Mucin in drug resistant ovarian 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 4554. doi:10.1158/1538-7445.AM2015-4554
652. Culture and Characterization of Tumor-Infiltrating Lymphocytes of the Syrian Hamster
Authors: Mikko Siurala, Markus Vähä-Koskela, Riikka Havunen, Siri Tähtinen, Simona Bramante, Suvi Parviainen, Akseli Hemminki
Journal: Molecular Therapy (2016)

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has developed into a promising treatment modality for metastatic cancer. However, preclinical animal models for studying TIL therapy are limited to mice and therefore we set out to culture and characterize TIL from another rodent species, the Syrian hamster. First, we examined the presence of CD4+ and CD8+ cells in six implantable syngeneic hamster tumors representing various histologies. A tumor type-dependent pattern of lymphocyte infiltration was observed, with CD8+ cells ranging from 0.08% to 0.93% (of all tumor cells) and CD4+ cells ranging from 0.17% to 3.25%. To establish TIL cultures, excised tumor fragments were cultured in high-dose human interleukin-2 (IL-2) for 10 days. Flow cytometric analyses of Day 10 TIL cultures revealed a predominance of CD4+ cells over CD8+ cells in all tumor types studied. In effector/target assays the TIL cultured from HapT1 (pancreatic adenocarcinoma) and RPMI 1846 (melanoma) exhibited tumor-specific cytolytic activity. In addition, MHC Class I blocking abrogated the cell killing of RPMI 1846 TIL, suggesting that cytotoxic CD8+ T-cells were responsible for the observed cytolytic activity. Only partial abrogation was seen with HapT1 TIL suggesting the presence of cytotoxic CD4+ T-cells in the TIL population, which is supported by the observation that HapT1 tumor cells express MHC Class II. To our knowledge, this is the first time tumor-infiltrating lymphocytes of the Syrian hamster have been cultured and characterized. Thorough immunophenotyping of hamster tumors and TIL cultures requires the development of new hamster-specific antibodies in addition to the currently available ones used in this study. In conclusion, our data supports the use of the Syrian hamster as a novel platform for testing TIL protocols in a species other than mouse or human.
Abstract 291: Targeting the stroma to hit the tumor: MMP11 as a novel target for cancer immunotherapy
Authors: Laura Luberto, Rita Mancini, Arianna Di Napoli, Daniela Peruzzi, Federica Mori, Giuseppe Roscilli, Emanuele Marra, Manuela Cappelletti, Gennaro Ciliberto, Luigi Aurisicchio
Journal: Cancer Research (2015)

Abstract Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that mediate a number of physiological and pathological processes, such as matrix degradation, tissue remodeling, inflammation and tumor metastasis. The objective of this study was to develop and characterize a vaccine targeting stromal antigens expressed by cancer associated fibroblasts (CAFs). We focused on MMP11 (or stromelysin 3, ST3), that has been detected primarily in CAFs and its expression correlates with aggressive clinical behavior and invasiveness of different types of carcinoma. We demonstrated that intramuscular injection of genetic vectors such as Adenovirus (Ad) and plasmid DNA encoding MMP11 engineered variants followed by in vivo electroporation (DNA-EP) resulted in breakage of immune tolerance and induction of both cell mediated and humoral immune response. Importantly, MMP11 vaccine was able to confer significant antitumoral protection in a chemically induced, MMP11 overexpressing colon cancer model both in prophylactic and therapeutic settings. To determine the mechanism of action of MMP11 vaccine, we have utilized IFNgamma- and μmicroMT-knock out mice, devoid of T- and B-cell immune response, respectively. Our results show that both arms of the immune response are important to confer the therapeutic effect. Moreover, MMP11 stromal vaccine showed synergic effects when combined with genetic vaccines targeting classic tumor associated antigens, such as telomerase reverse transcriptase (TERT) and carcinoembryonic antigen (CEA). Finally, to assess the immunogenicity and the safety of MMP11 vaccine in a large animal model, nonhuman primates have been vaccinated with Ad and DNA-EP. A strong immune response was measured with no detectable side effects. In addition, MMP11 detection and spontaneous immune responses in the blood of breast and prostate cancer patients further corroborate MMP11 as a valid target for immune intervention. Taken together, these data support the use of MMP11 as a potential candidate for cancer immunotherapy in human clinical trials. Citation Format: Laura Luberto, Rita Mancini, Arianna Di Napoli, Daniela Peruzzi, Federica Mori, Giuseppe Roscilli, Emanuele Marra, Manuela Cappelletti, Gennaro Ciliberto, Luigi Aurisicchio. Targeting the stroma to hit the tumor: MMP11 as a novel target for cancer immunotherapy. [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 291. doi:10.1158/1538-7445.AM2015-291
FLT3 Internal Tandem Duplication Is Associated with High Relapse Rate and Central Nervous System Involvement in Acute Promyelocytic Leukemia
Authors: Haruko Tashiro, Yoko Oka, Toshihiko Sugao, Ryosuke Shirasaki, Mitsuho Noguchi-Mizutani, Nobu Akiyama, Kazuo Kawasugi, Naoki Shirafuji
Journal: Blood (2008)