tbuckley/cabot-search huggingface dataset:
Randomized, phase II trial comparing carboplatin (C) and tri-weekly paclitaxel (tP) with C and weekly paclitaxel (wP) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: M. Maemondo, A. Inoue, S. Sugawara, T. Ishida, K. Usui, T. Abe, M. Kanbe, H. Watanabe, Y. Saijo, T. Nukiwa
Journal: Journal of Clinical Oncology (2008)

19046 Background: The appropriate platinum doublet regimen for elderly pts with advanced NSCLC is still matter of debate. Although previous randomized trial failed to show a survival benefit of C + wP against standard C + tP in advanced NSCLC, less toxic profile of C + wP may be favorable for elderly population. This elderly specific, randomized phase II study was conducted to evaluate the efficacy and safety of C + tP and C + wP for future large scale trials. Methods: Previously untreated elderly (≥70 years old) pts with advanced NSCLC were randomized to receive C (AUC 6, day1) + tP (200 mg/m2, day1) or C (AUC 6, day1) + wP (70 mg/m2, day1, 8, 15). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS) and toxicity profile. Assuming that ORR of 40% in eligible pts would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.05 and beta = 0.20, the estimated accrual was 36 pts in each arm. Results: From November 2004 to June 2007, 82 pts were enrolled from 12 institutions. All the pts were evaluable for safety and 81 pts were evaluable for efficacy. Patient characteristics were: Male/Female 69/13; median age 75 (range 70–87); Performance status 0/1 42/40; Stage IIIB/IV/postoperative recurrence 26/47/9. The median numbers of treatment cycles were 3 (range 1–6) in both arms. ORRs and disease control rates were 53% (95%CI: 38–68) and 88% for tP arm, and 55% (95%CI: 40–70) and 91% for wP arm. Median PFS on tP arm was 4.3 months and on wP arm was 4.9 months. Grade 3 peripheral neuropathy was observed only in tP arm (25%). Grade 3/4 neutropenia and febrile neutropenia were more frequent in tP arm (88% and 10%) than wP arm (41% and 2%). One treatment related death due to interstitial lung disease was observed in wP arm. Conclusions: C and wP is similarly effective and less toxic than C and tP in this study. Further evaluation of this regimen for elderly population with advanced NSCLC is warranted No significant financial relationships to disclose.
Inflammation Modifies the Paradoxical Association between Body Mass Index and Mortality in Hemodialysis Patients
Authors: Peter Stenvinkel, Iain A. Gillespie, Jamie Tunks, Janet Addison, Florian Kronenberg, Tilman B. Drueke, Daniele Marcelli, Guntram Schernthaner, Kai-Uwe Eckardt, Jürgen Floege, Marc Froissart, Stefan D Anker
Journal: Journal of the American Society of Nephrology (2015)

High body mass index (BMI) is paradoxically associated with better outcome in hemodialysis (HD) patients. Persistent inflammation commonly features in clinical conditions where the obesity paradox is described. We examined the relationship between BMI and mortality in HD patients, accounting for inflammation, in a historic cohort study of 5904 incident HD patients enrolled in 2007–2009 (312 facilities; 15 European countries) with ≥3 months of follow-up. Patients were classified by presence ( n =3231) or absence ( n =2673) of inflammation (C-reactive protein ≥10 mg/l and/or albumin ≤35 g/l). Patients were divided into quintiles by BMI (Q1–Q5: &lt;21.5, 21.5–24.0, &gt;24.0–26.4, &gt;26.4–29.8, and &gt;29.8 kg/m 2 , respectively). Noninflamed patients in BMI Q5 formed the reference group. During a median follow-up period of 36.7 months, 1929 deaths occurred (822 cardiovascular), with 655 patients censored for renal transplantation and 1183 for loss to follow-up. Greater mortality was observed in inflamed patients ( P &lt;0.001). In fully adjusted time-dependent analyses, the all-cause mortality risk in noninflamed patients was higher only in the lowest BMI quintile (hazard ratio [HR, 1.80; 95% confidence interval [95% CI], 1.26 to 2.56). No protective effect was associated with higher BMI quintiles in noninflamed patients. Conversely, higher BMI associated with lower all-cause mortality risk in inflamed patients (HR [95% CI] for Q1: 5.63 [4.25 to 7.46]; Q2: 3.88 [2.91 to 5.17]; Q3: 2.89 [2.16 to 3.89]; Q4: 2.14 [1.59 to 2.90]; and Q5: 1.77 [1.30 to 2.40]). Thus, whereas a protective effect of high BMI was observed in inflamed patients, this effect was mitigated in noninflamed patients.
Actin-resistant DNAse I Expression From Oncolytic Adenovirus Enadenotucirev Enhances Its Intratumoral Spread and Reduces Tumor Growth
Authors: Alison Tedcastle, Sam Illingworth, Alice Brown, Leonard W Seymour, Kerry D Fisher
Journal: Molecular Therapy (2015)

Spread of oncolytic viruses through tumor tissue is essential to effective virotherapy. Interstitial matrix is thought to be a significant barrier to virus particle convection between "islands" of tumor cells. One way to address this is to encode matrix-degrading enzymes within oncolytic viruses, for secretion from infected cells. To test the hypothesis that extracellular DNA provides an important barrier, we assessed the ability of DNase to promote virus spread. Nonreplicating Ad5 vectors expressing actin-resistant DNase (aDNAse I), proteinase K (PK), hyaluronidase (rhPH20), and chondroitinase ABC (CABC) were injected into established DLD human colorectal adenocarcinoma xenografts, transcomplemented with a replicating Ad5 virus. Each enzyme improved oncolysis by the replicating adenovirus, with no evidence of tumor cells being shed into the bloodstream. aDNAse I and rhPH20 hyaluronidase were then cloned into conditionally-replicating group B adenovirus, Enadenotucirev (EnAd). EnAd encoding each enzyme showed significantly better antitumor efficacy than the parental virus, with the aDNAse I-expressing virus showing improved spread. Both DNase and hyaluronidase activity was still measurable 32 days postinfection. This is the first time that extracellular DNA has been implicated as a barrier for interstitial virus spread, and suggests that oncolytic viruses expressing aDNAse I may be promising candidates for clinical translation.
Screening for amblyopia in preverbal children with photoscreening photographs
Authors: Patrick Y Tong, Erinn Enke-Miyazaki, Roger E Bassin, James M Tielsch, David R Stager, George R Beauchamp, Marshall M Parks
Journal: Ophthalmology (1998)

This study aimed to determine the ability of healthcare professionals and lay volunteers to grade photoscreening photographs.The study design was a cross-sectional study.One hundred children 3 years of age or younger received a complete ophthalmologic examination and were photographed using the Medical Technology Innovations (MTI) photoscreener. Twenty-six children had normal examination results, and the remaining 74 children had conditions that are of interest for pediatric screening, including strabismus, refractive error, media opacities, and ptosis. Eighteen volunteers, including pediatric ophthalmologists, pediatricians, ophthalmic technicians, health department nurses, Prevention of Blindness Society personnel, and Lions Club volunteers, graded each of the 100 photoscreening photographs.Sensitivity and specificity of vision screening and of photograph grading were measured.Results from various graders yielded sensitivities ranging from 37% to 88% and specificities ranging from 40% to 88%. No single grader achieved sensitivity and specificity both greater than 70%. The grading of the manufacturer's representative had a sensitivity of 43% and a specificity of 85%. Sensitivity decreased to 31% for strabismus and 18% for refractive error when the correct type of strabismus or refractive error was required to be considered true-positives. Results were not positively correlated with the ophthalmologic knowledge of the participant.The wide variability in sensitivities and specificities among graders indicates inconsistent photograph interpretation skills or deficient screening guidelines or both. For off-axis photoscreening as implemented by the MTI system to become a useful vision-screening method, additional photograph interpretation skill transfer may be beneficial, although not necessarily sufficient.
Situation of HIV infections and STIs in the United Kingdom in 2007
Authors: S Lattimore, Z Yin, L Logan, B Rice, A Thornton, D Molinar, G Leong, A Presanis, D De Angelis, N Gill, V Delpech
Journal: Eurosurveillance (2008)

In the United Kingdom (UK) in 2007, an estimated 77,400 persons were living with human immunodeficiency virus (HIV) of whom 28% are unaware of their infection. A total of 7,734 persons were newly diagnosed with HIV infection in 2007, of which 31% were diagnosed late. This highlights the need for wider HIV testing, especially in those areas with a high diagnosed prevalence, as recommended in recent national guidelines. Among newly diagnosed cases of HIV in 2007, 41% acquired their infection through sex between men (four in five of whom acquired their infection in the UK) and 55% through heterosexual contact (four in five of whom acquired their infection abroad, mainly in sub-Saharan Africa). Young persons aged 16 to 24 years are disproportionally affected by sexually transmitted diseases (STIs) accounting for 65% of genital chlamydia infections, 50% of cases of genital warts and 50% of cases of gonorrhoea that were diagnosed in 2007.
Impact of a Continuous Quality Improvement Initiative on Appropriate Use of Coronary Computed Tomography Angiography
Authors: Kavitha M. Chinnaiyan, Patricia Peyser, Tauqir Goraya, Karthikeyan Ananthasubramaniam, Michael Gallagher, Ann DePetris, Judith A. Boura, Ella Kazerooni, Chad Poopat, Mouaz Al-Mallah, Souheil Saba, Smita Patel, Steven Girard, Thomas Song, David Share, Gilbert Raff
Journal: Journal of the American College of Cardiology (2012)
A dysbiotic subpopulation of alcohol-dependent subjects
Authors: Philippe de Timary, Sophie Leclercq, Peter Stärkel, Nathalie Delzenne
Journal: Gut Microbes (2015)

The vast majority of studies that assessed the importance of biological factors for the development of psychiatric disorders focused on processes occurring at the brain level. Alcohol-dependence is a very frequent psychiatric disorder where psycho-pharmacological interventions are only of moderate efficacy. Our laboratory has recently described that a subpopulation of alcohol-dependent subjects, that accounted for approximately 40% of individuals tested, presented with an increased intestinal permeability, with a dysbiosis, with alterations in the metabolomic content of faeces--that could play a role in the increased permeability--and finally with a more severe profile of alcohol-dependence than the other non-dysbiotic subpopulation. In this addendum, we discuss the implications of our observations for the pathophysiology of alcohol dependence where we try to discriminate which addiction dimensions are likely related to the gut microbiota alterations and whether these alterations are the cause or the consequence of drinking habits.
Treatment of advanced neuroblastoma with supralethal chemotherapy, radiation, and allogeneic or autologous marrow reconstitution.
Authors: C S August, F T Serota, P A Koch, E Burkey, H Schlesinger, W L Elkins, A E Evans, G J D'Angio
Journal: Journal of Clinical Oncology (1984)

Ten children with recurrent metastatic (stage IV) neuroblastoma received local radiation therapy, supralethal chemotherapy, and total-body irradiation. Rescue with infusions of either allogeneic (four patients) or autologous (six patients) bone marrow followed. The drugs given to the first two patients were individualized combinations based on previous tumor responses. Both patients died with recurrent tumor three and nine months posttransplant. The eight remaining patients were treated more uniformly with local irradiation, VM-26, doxorubicin, melphalan (L-phenylalanine mustard), and 1,000-rad total-body irradiation in three fractions. Two of these patients had cardiac dysfunction and received no doxorubicin. Three children died in the immediate posttransplant period with disseminated fungal infections. A fourth relapsed and died nine months posttransplant. As of December 1, 1983, two children who received allogeneic marrow grafts have survived in complete remission for 54 and 36 months, and two children who received autologous marrow grafts have survived in complete remission for 35 and 22 months. These results suggest that relapsed metastatic neuroblastoma can be controlled by supralethal combinations of chemotherapy and irradiation coupled with bone-marrow rescue.
Progesterone receptor membrane component-1 regulates hepcidin biosynthesis
Authors: Xiang Li, David K. Rhee, Rajeev Malhotra, Claire Mayeur, Liam A. Hurst, Emily Ager, Georgia Shelton, Yael Kramer, David McCulloh, David Keefe, Kenneth D. Bloch, Donald B. Bloch, Randall T. Peterson
Journal: Journal of Clinical Investigation (2015)

Iron homeostasis is tightly regulated by the membrane iron exporter ferroportin and its regulatory peptide hormone hepcidin. The hepcidin/ferroportin axis is considered a promising therapeutic target for the treatment of diseases of iron overload or deficiency. Here, we conducted a chemical screen in zebrafish to identify small molecules that decrease ferroportin protein levels. The chemical screen led to the identification of 3 steroid molecules, epitiostanol, progesterone, and mifepristone, which decrease ferroportin levels by increasing the biosynthesis of hepcidin. These hepcidin-inducing steroids (HISs) did not activate known hepcidin-inducing pathways, including the BMP and JAK/STAT3 pathways. Progesterone receptor membrane component-1 (PGRMC1) was required for HIS-dependent increases in hepcidin biosynthesis, as PGRMC1 depletion in cultured hepatoma cells and zebrafish blocked the ability of HISs to increase hepcidin mRNA levels. Neutralizing antibodies directed against PGRMC1 attenuated the ability of HISs to induce hepcidin gene expression. Inhibiting the kinases of the SRC family, which are downstream of PGRMC1, blocked the ability of HISs to increase hepcidin mRNA levels. Furthermore, HIS treatment increased hepcidin biosynthesis in mice and humans. Together, these data indicate that PGRMC1 regulates hepcidin gene expression through an evolutionarily conserved mechanism. These studies have identified drug candidates and potential therapeutic targets for the treatment of diseases of abnormal iron metabolism.
Defining the Value of a Comparative Approach to Cancer Drug Development
Authors: Amy K. LeBlanc, Christina N. Mazcko, Chand Khanna
Journal: Clinical Cancer Research (2015)

Abstract Comparative oncology as a tool in drug development requires a deeper examination of the value of the approach and examples of where this approach can satisfy unmet needs. This review seeks to demonstrate types of drug development questions that are best answered by the comparative oncology approach. We believe common perceived risks of the comparative approach relate to uncertainty of how regulatory bodies will prioritize or react to data generated from these unique studies conducted in diseased animals, and how these new data will affect ongoing human clinical trials. We contend that it is reasonable to consider these data as potentially informative and valuable to cancer drug development, but as supplementary to conventional preclinical studies and human clinical trials particularly as they relate to the identification of drug-associated adverse events. Clin Cancer Res; 22(9); 2133–8. ©2015 AACR.
The Genetic Basis of Hydrocephalus
Authors: Maria Kousi, Nicholas Katsanis
Journal: Annual Review of Neuroscience (2016)

Studies of syndromic hydrocephalus have led to the identification of &gt;100 causative genes. Even though this work has illuminated numerous pathways associated with hydrocephalus, it has also highlighted the fact that the genetics underlying this phenotype are more complex than anticipated originally. Mendelian forms of hydrocephalus account for a small fraction of the genetic burden, with clear evidence of background-dependent effects of alleles on penetrance and expressivity of driver mutations in key developmental and homeostatic pathways. Here, we synthesize the currently implicated genes and inheritance paradigms underlying hydrocephalus, grouping causal loci into functional modules that affect discrete, albeit partially overlapping, cellular processes. These in turn have the potential to both inform pathomechanism and assist in the rational molecular classification of a clinically heterogeneous phenotype. Finally, we discuss conceptual methods that can lead to enhanced gene identification and dissection of disease basis, knowledge that will potentially form a foundation for the design of future therapeutics.
Modeling Human Bone Marrow Failure Syndromes Using Pluripotent Stem Cells and Genome Engineering
Authors: Moonjung Jung, Cynthia E Dunbar, Thomas Winkler
Journal: Molecular Therapy (2015)

The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases. The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases.
Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector
Authors: Sourav R Choudhury, Anne F Harris, Damien J Cabral, Allison M Keeler, Ellen Sapp, Jennifer S Ferreira, Heather L Gray-Edwards, Jacob A Johnson, Aime K Johnson, Qin Su, Lorelei Stoica, Marian DiFiglia, Neil Aronin, Douglas R Martin, Guangping Gao, Miguel Sena-Esteves
Journal: Molecular Therapy (2015)

Effective gene delivery to the central nervous system (CNS) is vital for development of novel gene therapies for neurological diseases. Adeno-associated virus (AAV) vectors have emerged as an effective platform for in vivo gene transfer, but overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. Here, we investigated the possibility of improving CNS transduction of existing AAV capsids by genetically fusing peptides to the N-terminus of VP2 capsid protein. A novel vector AAV-AS, generated by the insertion of a poly-alanine peptide, is capable of extensive gene transfer throughout the CNS after systemic administration in adult mice. AAV-AS is 6- and 15-fold more efficient than AAV9 in spinal cord and cerebrum, respectively. The neuronal transduction profile varies across brain regions but is particularly high in the striatum where AAV-AS transduces 36% of striatal neurons. Widespread neuronal gene transfer was also documented in cat brain and spinal cord. A single intravenous injection of an AAV-AS vector encoding an artificial microRNA targeting huntingtin (Htt) resulted in 33-50% knockdown of Htt across multiple CNS structures in adult mice. This novel AAV-AS vector is a promising platform to develop new gene therapies for neurodegenerative disorders.
Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease
Authors: Aranzazu Jauregui-Amezaga, Montserrat Rovira, Pedro Marín, Azucena Salas, Susana Pinó-Donnay, Faust Feu, J Ignasi Elizalde, Francesc Fernández-Avilés, Carmen Martínez, Gonzalo Gutiérrez, Laura Rosiñol, Enric Carreras, Alvaro Urbano, Miguel Lozano, Joan Cid, María Suárez-Lledó, Josep Mensa, Jordi Rimola, Sonia Rodríguez, Mari Carme Masamunt, Dolors Comas, Irene Ruíz, Anna Ramírez-Morros, Marta Gallego, Ingrid Ordás, Julian Panés, Elena Ricart
Journal: Gut (2015)

<h3>Objective</h3> To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn9s disease (CD). <h3>Design</h3> In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. <h3>Results</h3> 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (&gt;0.5×10<sup>9</sup>/L) was 11 days and for platelets (&gt;20×10<sup>9</sup>/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. <h3>Conclusions</h3> Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres.