tbuckley/cabot-search huggingface dataset:
Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses
Authors: Joseph A Katakowski, Gayatri Mukherjee, Samantha E Wilner, Keith E Maier, Michael Travis Harrison, Teresa P DiLorenzo, Matthew Levy, Deborah Palliser
Journal: Molecular Therapy (2015)

Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving "undruggable" targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205+ DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR. Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving "undruggable" targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205+ DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR.
Validation of the selected dose of aflibercept (VEGF Trap) plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a phase I clinical trial of patients (pts) with advanced solid tumors (STs): Preliminary results
Authors: C. Verslype, J. Spano, E. Van Cutsem, J. P. Grapin, V. Vandecaveye, J. Bloch, K. Soussan Lazard, S. Assadourian, S. Tejpar, D. Khayat
Journal: Journal of Clinical Oncology (2008)

14540 Background: Aflibercept (AF), a potent angiogenesis inhibitor fusion protein, is comprised of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG1. A phase I dose escalation study established the AF 4.0 mg/kg + I-LV5FU2 (standard dose) every 2 weeks (q2w) as the recommended dose to be confirmed in a feasibility study. Methods: This was a randomized, double blind feasibility study of AF (4.0 mg/kg) or placebo + I-LV5FU2 at cycle 1, followed in subsequent cy by AF (4.0 mg/kg) + I-LV5FU2 q2w in pts with solid tumors. Study endpoints were to confirm the AF dose, explore the safety, preliminary efficacy and antivascular activity (DCE MRI) of AF. DCE MRI was performed at cycle 1 and 2, all imagings were centrally reviewed. Results: 27 pts were treated in both arms (15 male/12 female), median age 54 [39–75], ECOG PS 0/1/2: 12/11/4, with 70% of colorectal cancers. All pts received prior chemotherapy (CT): median 3 [1–6], 21 pts were previously treated with an I-based regimen. Pts received a total of 205 (median 8 [1–18]) treatment cycles and the AF relative dose intensity was 92%. The main grade (Gr) 3–4 AF-related toxicity (% pts) was hypertension (HTN) (15%). Moderate (Gr2) HTN (26%), dysphonia (11%), epistaxis (4%) and proteinuria (4%) were observed. No Gr 4 was reported. One pt (colon cancer previously exposed to I-based CT) achieved partial response and 21 pts had stable disease. Conclusions: AF 4.0 mg/kg is safely combined with I-LV5FU2 and is the recommended dose for phase III trials. Signs of activity are reported. Updated safety and efficacy results from this ongoing study will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis
Somatic mutations of EGFR signal transducers and expression of tumor suppressor PTEN in biliary tract carcinoma
Authors: M. Aglietta, Y. Pignochino, G. Cavalloni, I. Sarotto, J. Penachioni, C. Zanon, G. Migliardi, W. Piacibello, M. Risio, A. Bardelli, F. Leone
Journal: Journal of Clinical Oncology (2007)

4582 Background: Biliary tract carcinomas express EGFR and are potential candidates to EGFR target therapies. We recently described somatic mutations of EGFR that can enhance MAPK or Akt activation (Clin Cancer Res, 2006). Some of them are identical to those previously reported to confer sensitivity to some tyrosine kinase inhibitors (TKIs) like erlotinib or gefitinib in lung cancer. Here we report a molecular analysis of EGFR transducers potentially involved in TKI response. Methods: In 49 samples of biliary tract carcinoma we performed mutational analysis of exons from 18 to 21 of EGFR, exons 9 and 20 of phosphatidylinositol 3’-kinase (PI3K), exon 2 of K-Ras, exon 15 of B-Raf and exons from 5 to 8 of PTEN. Nuclear PTEN expression was analyzed by immunohistochemistry and the expression in cancer cells was compared to that of normal cholangiocites. Results: Mutations of EGFR have been detected in 7 out of 49 samples (14.3%). One of them was a new stop-codon mutation. Five hotspot mutations of PI3K (codon 545, 546, 1048 and 1059) were found in 4 cases (8.2%); 3 cases (6.1%) had single mutations in K-Ras and 4 (8.2%) had the V599E mutation in B-Raf. In some samples, mutations of multiple trasducers were present simultaneously. PI3K mutations were significantly more frequent in EGFR mutated samples compared to wild type (28% vs. 4.7% respectively, p&lt;0.05). A single F271L mutation of PTEN was observed (2%). We did not find loss of nuclear PTEN in biliary tract carcinoma cells; rather, a stronger labelling intensity (score 2+ or 3+) was present in biliary tract carcinoma compared to normal cholangiocites (score 1+). Moreover, the median percentage of PTEN labeled nuclei in tumor cells was 31.8%, but in samples with activating EGFR mutation was 60%, suggesting that a compensatory change in the level of the phosphatase might counteract the EGFR activition. Conclusions: These results corroborate our previous finding of EGFR pathway activation in EGFR mutated biliary tract carcinoma and suggest that an accurate analysis of the entire series of EGFR transducers may be done before planning treatments with TKIs. No significant financial relationships to disclose.
Abstract 1318: A PCSK9 C-terminal Domain Binding Fab Inhibits PCSK9 Internalization and Restores LDL-uptake
Authors: Yan G Ni, Jon H Condra, Stefania Di Marco, Laura Orsatti, Xun Shen, Shilpa Pandit, Matthew J Bottomley, Lionello Ruggeri, Richard T Cummings, Rose M Cubbon, Joseph C Santoro, Timothy S Fisher, Paola Lo Surdo, Fabio Talamo, Dana D Wood, Holly A Hammond, Douglas Wisniewski, Cinzia Volpari, Leila Njimoluh, Sookhee Ha, Brian Hubbard, Andrea Carfi, Ayesha Sitlani
Journal: Circulation (2009)

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) binds to LDL receptor (LDLR) protein, which ultimately leads to LDLR degradation and inhibition of plasma LDL cholesterol (LDL-C) clearanc...
COPBLAM III: infusional combination chemotherapy for diffuse large-cell lymphoma.
Authors: D B Boyd, M Coleman, S W Papish, A Topilow, S K Kopel, B Bernhardt, J C Files, S Schwartz, M Gaynor, D McDermott
Journal: Journal of Clinical Oncology (1988)

COPBLAM III, a polychemotherapy regimen consisting of cyclophosphamide, infusional vincristine, prednisone, infusional bleomycin, doxorubicin, and procarbazine, was administered to 51 patients with diffuse large-cell lymphoma. Ninety-six percent of patients age 60 or younger achieved a complete response (CR); none have relapsed. Overall, 88% of patients are alive and well and potentially in the survival plateau. For patients greater than 60 years, CR was obtained in 73%, with 42% potentially in the survival plateau, the difference resulting in part from four relapses, three toxic deaths, and one presumed unrelated death. These results in the elderly were paralleled by a relatively reduced ability to tolerate therapy. Toxicity was primarily pulmonary, occurring in 39% of patients, two of whom died. With an overall CR rate of 84%, of which 92% are sustained at a median follow-up of 40 months, COPBLAM III represents a highly effective treatment in a sizeable cohort of patients.
Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.
Authors: J L Gajewski, G L Phillips, K A Sobocinski, J O Armitage, R P Gale, R E Champlin, R H Herzig, D D Hurd, S Jagannath, J P Klein, H M Lazarus, P L McCarthy, S Pavlovsky, F B Peterson, P A Rowlings, J A Russell, S M Silver, J M Vose, P H Wiernik, M M Bortin, M M Horowitz
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, &lt; 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.
Reconsidering Guidelines on the Use of Pneumococcal Vaccines in Adults 65 Years or Older
Authors: Michael Hochman, Pieter A. Cohen
Journal: JAMA Internal Medicine (2015)

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Resting Heart Rate and Heart Rate Reserve in Advanced Heart Failure Have Distinct Pathophysiologic Correlates and Prognostic Impact
Authors: Jan Benes, Martin Kotrc, Barry A Borlaug, Katerina Lefflerova, Petr Jarolim, Bela Bendlova, Antonin Jabor, Josef Kautzner, Vojtech Melenovsky
Journal: JACC Heart Failure (2013)
Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome
Authors: Koonlawee Nademanee, Hariharan Raju, Sofia V. de Noronha, Michael Papadakis, Laurence Robinson, Stephen Rothery, Naomasa Makita, Shinya Kowase, Nakorn Boonmee, Vorapot Vitayakritsirikul, Samrerng Ratanarapee, Sanjay Sharma, Allard C. van der Wal, Michael Christiansen, Hanno L. Tan, Arthur A. Wilde, Akihiko Nogami, Mary N. Sheppard, Gumpanart Veerakul, Elijah R. Behr
Journal: Journal of the American College of Cardiology (2015)

The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months. BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS.
Abstract 2622: Serotonin And Endothelin Increase L-type Calcium Channel Current In Pulmonary Artery Smooth Muscle Cells, Unrelated To Changes In Membrane Potential
Authors: Zhigang Hong, Jesus A Cabrera, Mohan Dutt, Basel Aloul, E. K Weir
Journal: Circulation (2008)

Serotonin (5-HT) and endothelin (ET-1) are both involved in the pathophysiology of idiopathic pulmonary arterial hypertension. In addition to the release of calcium (Ca ++ ) from the internal stores in the smooth muscle cells (SMCs), these agents stimulate entry of Ca ++ through the L-type Ca ++ channel. In isolated rat pulmonary resistance artery (PA) rings, 5-HT (10 μM) caused a contraction of 110 ± 14 % of the contraction elicited by 60 mM KCl. After inhibition of K V and K Ca channels by 4-AP and TEA, 5-HT caused a stronger contraction of 176 ± 4% (p&lt;0.01). Consequently, we studied the relationship of 5-HT- stimulated contraction to membrane potential (E m ) and L-type calcium current in rat resistance PASMCs. Contrary to expectation, 5-HT (1, 10, 100 μM) had no effect on I K or E m (n=5 for each). However, 5-HT (10 μM) increased L-type calcium current between E m -20 and +30 mV (n=7). This effect was inhibited by a PKC blocker (BIS-1, 3 μM), which also caused a marked reduction of 5-HT-stimulated contraction of PA rings (&gt;70% decrease at 10 μM 5-HT). In contrast to 5-HT, ET-1 (10 nM) reduced I K and caused membrane depolarization (from −41 ± 5 to −31 ± 3 mV, n=4). In addition to this effect, ET-1, like 5-HT, increased L-type calcium current over the same range of E m (n=7). This increase was inhibited by nifedipine (3 μM). These experiments indicate that both 5-HT and ET-1 increase calcium influx through the L-type calcium channel in a manner independent of E m . ET-1 has an additional effect of causing membrane depolarization, which also increases calcium entry through L-type channels by altering voltage gating of the channel.
Abstract 4136: Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based study
Authors: Sara Beiggi, Versha Banerji, Angela Deneka, Jane Griffith, Spencer Gibson, James Johnston
Journal: Cancer Research (2014)

Abstract Chronic Lymphocytic Leukemia (CLL) patients in Manitoba are either referred to the CancerCare Manitoba (CCMB) CLL clinic or receive care from other hematologists/general practitioners. However, it is unknown whether referral to the CLL-specialized clinic alters patients' outcome. All CLL/SLL diagnoses in Manitoba 2007-2011 were obtained from the Manitoba Cancer Registry to create an immunophenotipically confirmed population-based cohort. Referred patients to the CLL-specialized clinic were identified from the CCMB charts. Association between age and treatment was measured by chi-squared test. Hazard ratio (HR) was determined using Cox Proportional Hazard Regression model. Of 555 CLL/SLL diagnoses, 281 (51%) were referred to the CLL-specialized clinic. For referred and non-referred patients the median age was 68y (39-99) and 72y (45-96), treated patients were 77 (27%) and 31 (11%), time to first treatment was 5m (0-5.5y) and 3m (0-2.5y), respectively. M:F was 1.7:1 for both groups. CLL was the primary cause of death in both referred and non-referred patients (57% and 35%, respectively). Comorbidities such as cardiovascular diseases had equal contributions to mortality in both populations (7% and 9.5% in referred and non-referred patients, respectively). When patients older than 70 years were investigated, elderly patients that were referred to the clinic were more likely to receive treatment (p = 0.0002). When adjusted for age (≥80y HR 10.79, p: &amp;gt;0.0001; 71-79y HR 5.44, p: 0.0007; 62-70y HR 4.07, p: 0.0051; &amp;lt;62 HR 1.00), gender (male HR 1.61, p: 0.0414), pre-CLL cancer (HR 1.85, p: 0.0187) and post-CLL Cancer (HR 2.31 p: 0.0208), patients seen by CLL-specialists had a &amp;gt;2-fold increased OS compared to non-referred patients (HR 2.39, p: 0.0003) in the Manitoba population. In the non-referred population, there was a striking correlation between advancing age and decreasing OS. This correlation was almost eliminated in the referred population. Thus, patients seen in a specialized clinic have an improved survival compared to non-referred patients and this appears to be primarily related to improved OS in the elderly. Whether this observation is related to improved therapy/supportive care in the specialized clinic or to referral bias is under investigation. Citation Format: Sara Beiggi, Versha Banerji, Angela Deneka, Jane Griffith, Spencer Gibson, James Johnston. Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4136. doi:10.1158/1538-7445.AM2014-4136
Application of multiple-locus variable-number tandem-repeat analysis to determine clonal spread of toxin A-negative Clostridium difficile in a general hospital in Buenos Aires, Argentina
Authors: A. Goorhuis, M.C. Legaria, R.J. van den Berg, C. Harmanus, C.H.W. Klaassen, J.S. Brazier, G. Lumelsky, E.J. Kuijper
Journal: Clinical Microbiology and Infection (2009)
Home non-invasive ventilation service for patients with chronic respiratory failure
Authors: Shu Wah Steve Ng, Wai Yee Tsang, Yuen Yee Anna Chan, Lee Veronica Chan, Chung Ming Chu
Journal: European Respiratory Journal (2011)

Introduction: There is increasing use of Non-Invasive Ventilation (NIV) in the management of patients with chronic respiratory failure such as Chronic Obstructive Pulmonary Disease (COPD). It was estimated that patients requiring home mechanical ventilation was 2.9 per 100,000 populations in 2004 in Hong Kong. Most of them (94.8%) were treated by NIV. The domiciliary NIV program has been established in a local acute hospital to provide optimal and comprehensive care for these patients since 2004.  Methodology: The service was run by qualified Respiratory Nurses. The enhancement program has provided more structured, proactive and specialized NIV service. The key components of the service include patient registry, primary nurse model, clinical pathway, patient and carer empowerment, nurse clinic, quality assurance and 24-hours hotline.  Results: There were 145 patients recruited since 2005. The gender ratio was about 4 to 1 (117, 80.5% of male and 28, 19.3% of female) with mean age of 71.98±8.91. After receiving domiciliary NIV service, their attendance numbers in emergency department, unplanned admission and length of stay were significantly reduced.  Conclusions: The Domiciliary NIV service could provide holistic, continuous and cost-effective care for these high-risk patients with complex needs. It could reduce avoidable healthcare utilization of these patients.
Lower values of VEGF in the endometrial lining are a possible cause of reduced fertility in asthmatic patients
Authors: Elisabeth Juul Gade, Simon Francis Thomsen, Svend Lindenberg, Nick Macklon, Vibeke Backer
Journal: European Respiratory Journal (2014)

Objective: Using endometrial secretion analysis, we assessed whether altered inflammatory cytokine levels can be detected in the uterine environment in asthma patients, thereby providing a possible cause of reduced fertility in asthmatics.

Methods: Forty-four unexplained infertile women (aged 28-44) underwent asthma and allergy testing, questionnaires, endometrial secretion and blood samples in the mid-secretory phase of the menstrual cycle (day 19-23) during assisted reproduction. Differences in cytokines and growth factors were analyzed.

Results: Mean log-VEGF in uteri was lower in asthma patients compared with controls (2.29 vs. 2.70), p=0.028. This was mainly due to a lower value of VEGF among women with non-atopic asthma compared with women with atopic asthma (1.86 vs. 2.72, p=0.009) and with healthy controls (1.86 vs. 2.70, p=0.01). Asthma treatment status had no effect on VEGF levels in uteri. Serum high sensitivity (Hs)CRP was negatively correlated with VEGF in uteri. No other significant correlations were observed between peripheral blood values and markers found in uteri.

Conclusion: Asthma is associated with lower values of VEGF in the uterine lining, which might affect the receptiveness of the endometrium and thereby increase time to pregnancy. The effect appears to be associated with non-atopic asthma with general increased systemic inflammation.