tbuckley/cabot-search huggingface dataset:
Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier
Authors: Blake H. Albright, Claire M. Storey, Giridhar Murlidharan, Ruth M. Castellanos Rivera, Garrett E. Berry, Victoria J. Madigan, Aravind Asokan
Journal: Molecular Therapy (2017)

Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile. Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.
Las infecciones por Escherichia coli O157 y la leche sin pasteurizar
Authors: F Allerberger, M Wagner, P Schweiger, H P. Rammer, A Resch, M P Dierich, A W Friedrich, H Karch
Journal: Eurosurveillance (2001)

Este informe describe dos casos de infeccion por Escherichia coli O157 en ninos, uno de los cuales desarrollo sindrome hemolitico uremico (SHU). Ambos consumieron leche cruda de vaca o cabra en la semana anterior a la aparicion de su enfermedad. La subtipificacion molecular permitio identificar un aislamiento de Escherichia coli O157:H fermentadora de sorbitol procedente de una vaca lechera. Este aislamiento se diferencio de las cepas de O157:H productoras de toxina Shiga aisladas en un nino de 6 anos enfermo de SHU. Este resultado subraya la necesidad de buscar otras causas de infeccion, aunque el consumo de leche sin pasteurizar este documentado. En el segundo enfermo, fue imposible diferenciar los aislamientos de O157:H humanos no fermentadores de sorbitol de los aislamientos animales de cabras. El aislamiento en animales de contacto de cepas Escherichia coli O157:H no fermentadoras de sorbitol imposibles de diferenciar ratifica la asociacion entre el SHU y el consumo de leche cruda de cabra, y vuelve a resaltar la importancia de pasteurizar la leche.
SPRINT: Phase II study of the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN).
Authors: Andrea M. Gross, Pamela Wolters, Andrea Baldwin, Eva Dombi, Michael J. Fisher, Brian D. Weiss, AeRang Kim, Jaishri O'Neill Blakeley, Patricia Whitcomb, Marielle Holmblad, Staci Martin, Marie Claire Roderick, Scott M. Paul, Janet Therrien, Kara Heisey, Austin Doyle, Malcolm A. Smith, John Glod, Seth M. Steinberg, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2018)

10503 Background: PN in NF1 can cause substantial morbidity, and there are no approved medical therapies. In a phase I trial of selumetinib, 17/24 (71%) patients (pts) had a partial response (PR)(Dombi, et al. N Engl J Med 2016; 375:2550-2560). This open-label phase II study (NCT01362803) determines the PR rate of PN treated with selumetinib and changes in PN related morbidities. Methods: Patients 2-18 years old with NF1, inoperable PN and ≥ 1 PN related morbidity received selumetinib at the recommended phase II dose (25 mg/m2 PO BID) with continuous dosing (1 cycle = 28 days). Response was evaluated with volumetric MRI analysis (PR = target PN volume decrease ≥20%) and PN related morbidities (pain, disfigurement, functional morbidities) assessed with standardized evaluations after every 4 cycles. Results: Fifty children (30 male, median age 10.2 years, range 3.5, 17.4) enrolled. Disfigurement (n=44), motor dysfunction (n=33) and pain (n=28) were the most frequent PN related morbidities. As of November 5, 2017: median cycle number 19.5 (range 0, 29) with 38 pts remaining on treatment; median change in PN volume from baseline -27.7% (range -50.6%, 2.2%); best response PR (36 pts, 72%), stable disease (12 pts, 24%); 2 subjects (4%) had no re-staging. Of the 36 total PR, 32 were confirmed on ≥ two consecutive restaging scans and 22 continue to have a PR ≥ 1 year after it was first achieved. Between baseline and end of year 1 evaluations, parent and child-reported pain intensity and pain interference scores significantly improved (p <0.01), as did strength (0-5 scale) and range of motion (degrees) of affected muscle groups/joints (p < 0.01). The most frequent toxicities were nausea/vomiting, diarrhea, asymptomatic creatine kinase increase, acneiform rash and paronychia. Selumetinib dose was reduced in 12 pts, of which 5 were removed from treatment. Conclusions: The response rate from this study (72%) confirms our previously observed response rate (71%). Most responses were sustained ≥6 months. Improvements in PN related pain and motor impairment demonstrate that selumetinib can provide clinical benefit. Data validation and further analyses are ongoing. Clinical trial information: NCT01362803.
Dermal Hyperneury and Multiple Sclerotic Fibromas in Multiple Endocrine Neoplasia Type 2A Syndrome
Authors: Victoria Alegría-Landa, Margarita Jo-Velasco, Mercedes Robledo, Luis Requena
Journal: JAMA Dermatology (2017)

Multiple endocrine neoplasia type 2 (MEN 2) syndrome is an autosomal dominant, hereditary cancer disorder caused by germline mutations in the RET (formerly MEN2A, MEN2B) proto-oncogene located on chromosomal band 10q11.21. Two distinct clinical forms have been described as the following phenotypes: multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B) syndromes. The common and necessary nexus that defines these 2 phenotypes is the presence of medullary thyroid carcinoma (MTC). The familial MTC type of MEN 2 syndrome was included within the spectrum of MEN 2A syndrome. Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas.To describe a family with cutaneous manifestations not previously described in patients with MEN 2A syndrome and to discuss the association of this disorder with Cowden syndrome.Clinicopathologic correlation of cutaneous lesions and genetic studies in 11 members of a family with familial MTC.Cutaneous lesions were histopathologically and immunohistochemically studied. Genetic screening for a germline mutation at the RET gene was performed in 11 family members.Identification of cutaneous lesions not previously described in patients with MEN 2A syndrome.This family of 11 individuals with familial MTC type of MEN 2A syndrome demonstrated the moderate risk RET p.Val804Met (protein valine at residue 804 replaced by methionine) genetic mutation, with 2 of the relatives presenting with dermal hyperneury, cutaneous lesions classically described in MEN 2B syndrome, and 1 relative also showing multiple sclerotic fibromas, a cutaneous manifestation of PTEN (phosphatase and tensin homologue) hamartoma-tumor syndrome.Dermal hyperneury and multiple sclerotic fibromas should be added to the list of cutaneous manifestations of patients with the familial MTC type of MEN 2A syndrome.
Agreement of the Resting Distal to Aortic Coronary Pressure With the Instantaneous Wave-Free Ratio
Authors: Yuhei Kobayashi, Nils P. Johnson, Frederik M. Zimmermann, Nils Witt, Colin Berry, Allen Jeremias, Bon-Kwon Koo, Giovanni Esposito, Gilles Rioufol, Seung-Jung Park, Takeshi Nishi, Dong-Hyun Choi, Keith G. Oldroyd, Emanuele Barbato, Nico H.J. Pijls, Bernard De Bruyne, William F. Fearon
Journal: Journal of the American College of Cardiology (2017)
A Novel DNA Aptamer for Dual Targeting of Polymorphonuclear Myeloid-derived Suppressor Cells and Tumor Cells
Authors: Haoran Liu, Junhua Mai, Jianliang Shen, Joy Wolfram, Zhaoqi Li, Guodong Zhang, Rong Xu, Yan Li, Chaofeng Mu, Youli Zu, Xin Li, Ganesh L. Lokesh, Varatharasa Thiviyanathan, David E. Volk, David G. Gorenstein, Mauro Ferrari, Zhongbo Hu, Haifa Shen
Journal: Theranostics (2017)

Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. Methods: In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through in vivo selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. Results: T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. Conclusion: The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.
A precision therapy against cancers driven by <i>KIT/PDGFRA</i> mutations
Authors: Erica K. Evans, Alexandra K. Gardino, Joseph L. Kim, Brian L. Hodous, Adam Shutes, Alison Davis, Xing Julia Zhu, Oleg Schmidt-Kittler, Doug Wilson, Kevin Wilson, Lucian DiPietro, Yulian Zhang, Natasja Brooijmans, Timothy P. LaBranche, Agnieszka Wozniak, Yemarshet K. Gebreyohannes, Patrick Schöffski, Michael C. Heinrich, Daniel J. DeAngelo, Stephen Miller, Beni Wolf, Nancy Kohl, Timothy Guzi, Nicholas Lydon, Andy Boral, Christoph Lengauer
Journal: Science Translational Medicine (2017)

BLU-285 is a selective and potent mutant KIT and PDGFRA inhibitor active in both preclinical and clinical settings.
Uric acid and incident dementia: a population-based cohort study
Authors: Young Ho Lee, Gwan Gyu Song
Journal: Annals of the Rheumatic Diseases (2017)

We read with great interest the article by Latourte and colleagues,1 regarding the effect of serum uric acid (SUA) level on the incidence of dementia. This large population-based prospective cohort study with 12 years of follow-up demonstrated that high SUA levels were associated with increased risk of dementia, especially vascular or mixed dementia. However, some issues deserve comment. The results reported by Latourte et al differ from those of another prospective population-based cohort study,2 which demonstrated that higher …
Epidémie de légionellose dans deux groupes de touristes voyageant dans des campings, France et Espagne, juin 1996
Authors: A Infuso, B Hubert, D Dumas, M Reyrolle, S De Mateo, C Pelaz, C Hemery, I Pérez
Journal: Eurosurveillance (1997)

Le 11 juin 1996, trois cas suspects de legionellose parmi un groupe de 42 touristes hollandais ont ete rapportes par l'hopital de Millau, dans le sud-ouest de la France, aux autorites sanitaires locales. Depuis le 15 mai, ce groupe (groupe 1) voyageait en caravanes et stationnait sur differents terrains de camping en France et en Espagne. Le 15 juin, 2 personnes d'un deuxieme groupe de 52 touristes hollandais (groupe 2) qui suivait le meme voyage organise a une semaine d'intervalle, etaient hospitalisees a Millau pour une pneumonie. Ce rapport resume les enquetes epidemiologiques et environnementales entreprises pour identifier la source de l'infection.
Abstract 11854: Nationwide In-hospital Outcomes of Pregnancy in Women With Single Ventricle Congenital Heart Disease
Authors: Ronnie T Collins, Adam Sandlin, Di Chang, Anthony Goudie, James M Robbins
Journal: Circulation (2016)

Introduction: Most patients with single ventricle (SV) congenital heart disease (CHD) are expected to survive to adulthood. Women with SV are often counseled against pregnancy; however, data on pregnancies in these women are lacking. We sought to evaluate in-hospital outcomes of pregnancy in women with SV. Methods: We used nationally representative data from 1998 to 2012 Nationwide Inpatient Sample database to identify patients ≥ 18 years of age admitted to the hospital with International Classification of Diseases-9th Revision codes for an intrauterine pregnancy and a diagnosis of either hypoplastic left heart syndrome, tricuspid atresia or common ventricle. A matched comparison group without a diagnosis of CHD or pulmonary hypertension was identified from the database. National estimates of hospitalizations were calculated. Length of stay (LOS), total hospital charges, and cardiovascular complications were analyzed and compared between groups. Charge data were adjusted to 2012 dollars. Results: There were 310 admissions of pregnant women with SV (63% with deliveries) and 1547 admissions in the control group (91% with deliveries). There was no change in the annual number of SV pregnancies during the study period. Vaginal delivery was more common in SV (74% vs 72%, p&lt;0.001). LOS (4.6 [0.98] days vs 2.5 [0.07], p&lt;0.001) and charges ($38,627 [11,918] vs $13,880 [631], p&lt;0.0001) were higher in SV. SV deliveries occurred more commonly in teaching hospitals (78% vs 51%, p&lt;0.001). Complications occurred in nearly all SV admissions and were more common in SV compared to controls. (Table) There were no deaths in either group. Conclusions: Pregnancies in women with SV are associated with increased hospital resource utilization and cardiovascular complications, though in-hospital pregnancy related death is rare. Vaginal delivery is common in these patients. These data suggest that pregnancy and vaginal delivery are well tolerated in women with SV.
Mechanism of apoptosis induction by chemical inhibitors of bcl-2 in acute leukemia cells
Authors: Marina Konopleva, Rooha Contractor, Peter P. Ruvolo, Xingming Deng, Ismael J. Samudio, Yue-Xi Shi, Teresa McQueen, Rui-Yu Wang, Wendy D. Schober, Xiaoyang Ling, Frank C. Marini, David Harris, Zeev Estrov, James McCubrey, W. Stratford May, Michael Andreeff
Journal: Cancer Research (2006)

4864   Bcl-2 family proteins are key regulators of apoptosis and are known to promote tumorigenesis and chemoresistance. Bcl-2 proteins are critical for cell survival and overexpressed in many tumors. ABT-737 is a small molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia (AML) blast, progenitor and stem cells at nanomolar concentrations without affecting normal hematopoietic cells. The BH3 mimetic induced the disruption of Bcl-2:Bax and activation of the intrinsic apoptotic pathway. ABT-737 works synergistically with chemotherapeutic agents such as ara-C and doxorubicin, but its activity was largely diminished in cells overexpressing Mcl-1 or displaying phosphorylated Bcl-2. NSF.N1/H7 cells stably transfected with phosphomimetic T69E/S70E/S87E (EEE) Bcl-2 mutants were resistant to ABT-737 (IC 50 >500 nM) as compared to cells expressing wt-Bcl-2 or the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutants (IC 50s  of 50 and 25 nM). Consistent with a mechanism whereby increased Bcl2 phosphorylation impedes ABT-737 suppression of Bcl2 dimerization with Bax, ABT-737 potently blocked Bcl2:Bax association in cells expressing exogenous WT Bcl2 and AAA mutant Bcl2 but not in cells expressing exogenous phosphomimetic EEE mutant Bcl2. Since the S70E phosphorylation site of Bcl-2 is a known ERK substrate, we examined combined effects of ABT-737 and MEK inhibitor PD98059 in OCI-AML3 cells resistant to ABT-737 alone. The combined activity of PD98059 and ABT-737 revealed a striking synergistic interaction between the MEK inhibitor and BH3 mimetic, with combination indices (CI) of 0.08±0.003. siRNA to Mcl-1 strikingly sensitized OCI-AML3 cells to ABT-induced apoptosis, suggesting that loss of Mcl-1 expression as a result of suppression of ERK may also be involved in the ability of PD98059 to enhance ABT-737-induced apoptosis. We have further demonstrated that ABT-737 reduced leukemia burden and prolonged survival of mice in an  in vivo  mouse model. These findings suggest that ABT-737 could be a highly effective anti-leukemia agent with a unique mode of action.
Acquiring new N-glycosylation sites in variable regions of immunoglobulin genes by somatic hypermutation is a common feature of autoimmune diseases
Authors: Annie Visser, Nishath Hamza, Frans G M Kroese, Nicolaas A Bos
Journal: Annals of the Rheumatic Diseases (2017)

With great interest, we read the contribution of Vergroesen et al that was published recently in Annals of the Rheumatic Diseases .1 In this manuscript, the authors describe the observation that immunoglobulin variable (V) region heavy and light chain transcripts from anti-citrullinated protein antibody (ACPA) IgG-expressing B cells in patients with rheumatic arthritis (RA) contain N-glycosylation sites (Nglycs) acquired by somatic hypermutation, whereas these acquired Nglycs (ac-Nglycs) were absent in tetanus toxoid (TT) specific B cells of healthy individuals. The authors postulate that the introduction of ac-Nglycs generates selective advantages that allow ACPA-expressing B cells to escape from classical selection mechanisms in germinal centres. We agree with the authors that this is an important finding which may have important implications for understanding citrulline-specific immunity in RA.

Here we would like to stress that ac-Nglycs, as a consequence of somatic hypermutation, might be important for RA and for many other rheumatoid and non-rheumatoid autoimmune diseases. We have shown previously2 increased numbers of IgG encoding immunoglobulin variable heavy region gene (IGHV) transcripts with ac-Nglycs derived from B cells and plasma cells residing in the inflamed parotid salivary gland of patients with primary Sjogren’s syndrome (pSS) compared with non-pSS sicca controls (24% vs 6%). Importantly, in pSS the IgG encoding transcripts exhibited …
De novo versus nevus-associated melanomas: Differences in associations with prognostic indicators and survival.
Authors: Rachel M. Cymerman, Kun Wang, Era C. Murzaku, Lauren A. Penn, Iman Osman, Yongzhao Shao, David Polsky
Journal: Journal of Clinical Oncology (2015)

9025 Background: Although 20%-30% of melanomas may be histopathologically “nevus-associated,” implying direct transformation of a nevus into melanoma, the majority of melanomas arise in clinically normal skin with no detectable precursor lesion. We aimed to determine whether nevus-associated and de novo melanomas differ in their associations with histopathologic features and survival. Methods: 1,048 melanoma patients prospectively enrolled in the NYU Melanoma Cooperative Group registry between 1972 and 1982 (NYU1) were analyzed to detect associations between type of melanoma (de novo vs nevus-associated) and age, anatomic site, ulceration, thickness, mitotic index, histological type, stage, and survival. We tested the significant associations in a replication cohort of 1,202 melanoma patients prospectively enrolled between 2002 and 2009 in the NYU Interdisciplinary Melanoma Cooperative Group registry (NYU2). Results: In the NYU1 dataset, de novo melanomas were more likely to be associated with older age (54 vs 47 years, p < 0.01), non-axial location (OR 1.53, p < 0.01), tumor thickness > 1.0mm (OR 1.95, p < 0.01), ulceration (OR 1.61, p = .026), nodular subtype (OR 2.79, p < 0.01), stage > 1 (OR 2.35, p < 0.01), and shorter overall survival (p < 0.01). In the NYU2 replication dataset, de novo melanoma was again significantly associated with older age (61 vs 54 years, p < 0.01), non-axial location (OR 2.29, p < 0.01), tumor thickness > 1.0mm (OR 2.22, p < 0.01), ulceration (OR 2.92 p < 0.01), nodular subtype (OR 2.23, p < 0.01), stage > 1 (OR 2.43, p < 0.01), and shorter overall survival (p < 0.01). In multivariate analysis, de novo histopathology was an independent, poor prognostic indicator in the NYU2 cohort only (HR = 1.69, p < 0.01). The NYU2 cohort has patients with thinner tumors (56.2% have tumors < 1.0mm) compared to the NYU1 cohort (41.8% have tumors < 1.0mm), which may contribute to the differing impact of the de novo histopathology on the survival models for these cohorts. Conclusions: These data suggest that de novo melanomas may be more aggressive than nevus-associated melanomas, and may differ in their molecular pathogenesis. These findings may also have implications for early detection programs.
Investigating Low-Velocity Fluid Flow in Tumors with Convection-MRI
Authors: Simon Walker-Samuel, Thomas A. Roberts, Rajiv Ramasawmy, Jake S. Burrell, Sean Peter Johnson, Bernard M. Siow, Simon Richardson, Miguel R. Gonçalves, Douglas Pendse, Simon P. Robinson, R. Barbara Pedley, Mark F. Lythgoe
Journal: Cancer Research (2018)

Abstract Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers. Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.