tbuckley/cabot-search huggingface dataset:
Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity
Authors: Qing Zhou, Yilin Hou, Li Zhang, Jianlin Wang, Youbei Qiao, Songyan Guo, Li Fan, Tiehong Yang, Lin Zhu, Hong Wu
Journal: Theranostics (2017)

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs.In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency.The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion.In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release.The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time.While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization.Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell.Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.
Treatment of Primary Cutaneous Marginal Zone B-Cell Lymphomas with Intralesional Rituximab
Authors: Eva Domingo Domenech, Queralt Salas, Octavio Servitje, Fina Climent, Helena Pomares, Ana Lucas, Carmen Aguilera, Alessandra Comai, Santiago Mercadal, Eva Gonzalez Barca, Anna Sureda
Journal: Blood (2016)
Breastfeeding, maternal asthma and wheezing in the first year of life: a longitudinal birth cohort study
Authors: Meghan B. Azad, Lorena Vehling, Zihang Lu, David Dai, Padmaja Subbarao, Allan B. Becker, Piushkumar J. Mandhane, Stuart E. Turvey, Diana L. Lefebvre, Malcolm R. Sears
Journal: European Respiratory Journal (2017)

The impact of breastfeeding on respiratory health is uncertain, particularly when the mother has asthma. We examined the association of breastfeeding and wheezing in the first year of life.We studied 2773 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Caregivers reported on infant feeding and wheezing episodes at 3, 6 and 12 months. Breastfeeding was classified as exclusive, partial (supplemented with formula or complementary foods) or none.Overall, 21% of mothers had asthma, 46% breastfed for at least 12 months and 21% of infants experienced wheezing. Among mothers with asthma, breastfeeding was inversely associated with infant wheezing, independent of maternal smoking, education and other risk factors (adjusted rate ratio (aRR) 0.52; 95% CI 0.35-0.77 for ≥12 versus <6 months breastfeeding). Compared with no breastfeeding at 6 months, wheezing was reduced by 62% with exclusive breastfeeding (aRR 0.38; 95% CI 0.20-0.71) and by 37% with partial breastfeeding supplemented with complementary foods (aRR 0.63; 95% CI 0.43-0.93); however, breastfeeding was not significantly protective when supplemented with formula (aRR 0.89; 95% CI 0.61-1.30). Associations were not significant in the absence of maternal asthma (p-value for interaction <0.01).Breastfeeding appears to confer protection against wheezing in a dose-dependent manner among infants born to mothers with asthma.
Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study
Authors: Wei Li, Tohti Amet, Yanyan Xing, Dennis Yang, Suthat Liangpunsakul, Puneet Puri, Patrick S. Kamath, Arun J. Sanyal, Vijay H. Shah, Barry P. Katz, Svetlana Radaeva, David W. Crabb, Naga Chalasani, Qigui Yu
Journal: Hepatology (2017)

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL‐6], IL‐8, interferon gamma–induced protein 10, IL‐4, IL‐9, IL‐10, fibroblast growth factor 2, IL‐7, IL‐15, and transforming growth factor alpha) but lower levels of the anti‐inflammatory macrophage‐derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon‐gamma in response to T‐cell stimulation. Up‐regulated IL‐6, IL‐8, CD38, and CD69 and down‐regulated macrophage‐derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of macrophage‐derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL‐8, IL‐10, fibroblast growth factor 2, and IL‐7 remained higher. Conclusion : AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (H epatology 2017;66:575–590).
Effective Combination of CPX-351 with FLT3 Inhibitors in AML Blasts Harboring the FLT3-ITD Mutation
Authors: David K. Edwards, Nathalie Javidi-Sharifi, Angela Rofelty, Claire Rosenfeld, Riley Roth-Carter, Paul Tardi, Lawrence Mayer, Jeffrey W. Tyner
Journal: Blood (2016)
Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells
Authors: Finn Hawkins, Philipp Kramer, Anjali Jacob, Ian Driver, Dylan C. Thomas, Katherine B. McCauley, Nicholas Skvir, Ana M. Crane, Anita A. Kurmann, Anthony N. Hollenberg, Sinead Nguyen, Brandon G. Wong, Ahmad S. Khalil, Sarah X.L. Huang, Susan Guttentag, Jason R. Rock, John M. Shannon, Brian R. Davis, Darrell N. Kotton
Journal: Journal of Clinical Investigation (2017)

It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1-expressing (NKX2-1+) precursor cells. However, this hypothesis has not been formally tested owing to an inability to purify or track these progenitors for detailed characterization. Here we have engineered and developmentally differentiated NKX2-1GFP reporter pluripotent stem cells (PSCs) in vitro to generate and isolate human primordial lung progenitors that express NKX2-1 but are initially devoid of differentiated lung lineage markers. After sorting to purity, these primordial lung progenitors exhibited lung epithelial maturation. In the absence of mesenchymal coculture support, this NKX2-1+ population was able to generate epithelial-only spheroids in defined 3D cultures. Alternatively, when recombined with fetal mouse lung mesenchyme, the cells recapitulated epithelial-mesenchymal developing lung interactions. We imaged these progenitors in real time and performed time-series global transcriptomic profiling and single-cell RNA sequencing as they moved through the earliest moments of lung lineage specification. The profiles indicated that evolutionarily conserved, stage-dependent gene signatures of early lung development are expressed in primordial human lung progenitors and revealed a CD47hiCD26lo cell surface phenotype that allows their prospective isolation from untargeted, patient-specific PSCs for further in vitro differentiation and future applications in regenerative medicine.
Response-Adapted Therapy for Newly Diagnosed Myeloma
Authors: Frederic J. Reu, Tomas Radivoyevitch, Jason Valent, Chad Cummings, Katherine Tullio, Debbie Hastings, Beth M Faiman, Kimberly Hamilton, Janice Reed, Mary Ann Karam, Matt Kalaycio, Hien K. Liu, Christy Samaras, Brian J. Bolwell, Mitchell R. Smith
Journal: Blood (2016)
De Novo and Secondary Acute Myeloid Leukemia, Real World Data on Outcomes from the French Nord-Pas-De-Calais Picardie Acute Myeloid Leukemia Observatory
Authors: Loïc Renaud, Olivier Nibourel, Celine Berthon, Christophe Roumier, Céline Rodriguez, Cecile Frimat, Catherine Roche-Lestienne, Aline Renneville, Bruno Quesnel, Claude Preudhomme
Journal: Blood (2016)
Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons
Authors: Maroof M. Adil, Tandis Vazin, Badriprasad Ananthanarayanan, Gonçalo M.C. Rodrigues, Antara T. Rao, Rishikesh U. Kulkarni, Evan W. Miller, Sanjay Kumar, David V. Schaffer
Journal: Biomaterials (2017)
CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice
Authors: Sreya Bagchi, Ying He, Hong Zhang, Liang Cao, Ildiko Van Rhijn, D. Branch Moody, Johann E. Gudjonsson, Chyung-Ru Wang
Journal: Journal of Clinical Investigation (2017)

A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.
Recipient-Derived BAFF and Alloantigen Synergistically Activate B Cells in Murine Chronic Gvhd
Authors: Wei Jia, Jonathan C. Poe, Hsuan Su, Glenn K Matsushima, Jeffrey Rathmell, Kazuhiro Imai, Nancy J Reyes, Diana M Cardona, Sarah Anand, Divino Deoliveira, Zhiguo Li, Daniel R Saban, Benny J. Chen, Nelson J. Chao, Stefanie Sarantopoulos
Journal: Blood (2016)
HLA-Haploidentical Donors Seem to be Not Inferior to HLA-Identical Sibling Donors for Hematopoietic Stem Cell Transplantation of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)?
Authors: Feng Chen, Depei Wu, XiaoWen Tang, Miao Miao, Chengcheng Fu, Huiying Qiu, Shengli Xue, Xiao Ma, Zhengming Jin
Journal: Blood (2016)
Induced membrane technique: Advances in the management of bone defects
Authors: Weifeng Han, Jie Shen, Hongri Wu, Shengpeng Yu, Jingshu Fu, Zhao Xie
Journal: International Journal of Surgery (2017)

Management of bone defects caused by trauma, osteomyelitis, and tumors is challenging, with many controversies over the optimal reconstruction method. Masquelet discovered induced membrane in management of large diaphyseal defects accidentally, and developed this technique with a concept of induced membrane. Induced membrane technique holds great potential for the reconstruction of bone defects, alternatively to manage this clinical challenge quiet easily. Induced membrane has unique structural characteristics and biological properties, which render this technique has an advantage of the time to bone healing is relatively independent of the length of bone defect. Herein, we reviewed the latest advances made in induced membrane technique and highlighted the concept of induced membrane in the management of bone defects.
Deciphering the Genic Basis of Yeast Fitness Variation by Simultaneous Forward and Reverse Genetics
Authors: Calum J. Maclean, Brian P.H. Metzger, Jian-Rong Yang, Wei-Chin Ho, Bryan Moyers, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2017)

The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding the genetic basis of phenotypic variation in natural populations is limited by inefficient association mapping due to strong and complex population structure. To overcome this challenge, we generated genome sequences for 85 strains and performed a comprehensive population genomic survey of a total of 190 diverse strains. We identified considerable variation in population structure among chromosomes and identified 181 genes that are absent from the reference genome. Many of these nonreference genes are expressed and we functionally confirmed that two of these genes confer increased resistance to antifungals. Next, we simultaneously measured the growth rates of over 4,500 laboratory strains, each of which lacks a nonessential gene, and 81 natural strains across multiple environments using unique DNA barcode present in each strain. By combining the genome-wide reverse genetic information gained from the gene deletion strains with a genome-wide association analysis from the natural strains, we identified genomic regions associated with fitness variation in natural populations. To experimentally validate a subset of these associations, we used reciprocal hemizygosity tests, finding that while the combined forward and reverse genetic approaches can identify a single causal gene, the phenotypic consequences of natural genetic variation often follow a complicated pattern. The resources and approach provided outline an efficient and reliable route to association mapping in yeast and significantly enhance its value as a model for understanding the genetic mechanisms underlying phenotypic variation and evolution in natural populations.
FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Authors: Susanna Søberg, Camilla H. Sandholt, Naja Z. Jespersen, Ulla Toft, Anja L. Madsen, Stephanie von Holstein-Rathlou, Trisha J. Grevengoed, Karl B. Christensen, Wender L.P. Bredie, Matthew J. Potthoff, Thomas P.J. Solomon, Camilla Scheele, Allan Linneberg, Torben Jørgensen, Oluf Pedersen, Torben Hansen, Matthew P. Gillum, Niels Grarup
Journal: Cell Metabolism (2017)
<sup>177</sup>Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice
Authors: Cindy J. Choy, Xiaoxi Ling, Jonathan J. Geruntho, Sophia K. Beyer, Joseph D. Latoche, Beatrice Langton-Webster, Carolyn J. Anderson, Clifford E. Berkman
Journal: Theranostics (2017)

Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature.One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance.In order to overcome this pharmacokinetic challenge, we outfitted a 177 Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401).The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177 Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores.A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds.While both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection.This increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.
Overcoming resistance mechanisms in a study of cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Fatima Karzai, Ravi Amrit Madan, Marc Robert Theoret, Philip M. Arlen, Julius Strauss, Guinevere Chun, Anna Couvillon, Nancy Harold, Clara Chen, Nancy Ann Dawson, Andrea Borghese Apolo, Seth M. Steinberg, Jane B. Trepel, John Joseph Wright, Douglas K. Price, James L. Gulley, William Douglas Figg, William L. Dahut
Journal: Journal of Clinical Oncology (2015)

e16032 Background: D improves survival in mCRPC, but benefits are modest. Emerging clinical data suggests mCRPC patients (pts) treated with anti-androgen therapy like abiraterone (AA) or enzalutamide (ENZA) have decreased responses to susequent therapy with D due to cross-resistance in the androgen pathway targeted by D, AA, and ENZA(van Soest et al, Eur J Cancer 49:18, 2013). Combining D with multikinase inhibitor C could potentially minimize tumor resistance by targeting different cellular signaling pathways without overlapping toxicities. Methods: D-naive pts receive D at 75 mg/m2 IV, day 1 of a 21 day cycle, P at 5 mg po q12 hours, C at 3 dose levels: 20 mg, 40, or 60 mg po daily until the maximum tolerated dose (MTD) is defined. In Phase II, pts who have progressed on AA or ENZA, are randomized to a two arm cohort comparing D+C to D with PFS as endpoint. Results: 19 pts have been accrued on phase I; 4 at 20 mg C, 8 at 40 mg C, and 7 at 60 mg C. On the phase II portion, 4 pts have been randomized to D, 3 pts to D + C. Median age is 68 (44-84 yrs). Median baseline PSA is 103.5 (0.01-754.1 ng/mL). Median Gleason score = 9 (7-10). Median number of cycles = 8.5 (1-37). 6 pts have PS of 0 and 20 pts have a PS of 1. 9 pts have bone only disease and 16 pts have bone and soft tissue (STD). 1 pt has STD only. Most common grade 2 and grade 3 adverse events (AEs) possibly related to C are: hand/foot syndrome (4/16), oral mucositis (4/16), hypophosphatemia (4/16), and fatigue (3/16). The MTD of C is 40 mg daily + D. On phase I, 13 patients previously treated with AA, the median potential follow up is 12.4 months. 9 month PFS is 60.5% (95% CI: 34.0%-82.0%). Conclusions: D plus P may have limited benefits after disease progression on AA as seen in 3 retrospective analyses demonstrating a median PFS of 4.6 months or less (Mezynski J, et al. Ann Oncol 23;11, 2012) (Aggarwal R, et al. Clin Genitourin Cancer 12;5, 2014) (Schweizer MT, et al. Eur Urol 66;4, 2014). PFS results seen in this trial compare favorably to historical data of treatment with D after progression on AA, suggesting the addition of C to D may help overcome acquired resistance. Further studies will assess if there is a molecular signature that identifies pts benefiting from C+D. Clinical trial information: NCT01683994.
Sacubitril–Valsartan in Heart Failure
Authors: Bennett E. Werner
Journal: Annals of Internal Medicine (2017)

Letters2 May 2017Sacubitril–Valsartan in Heart FailureBennett E. Werner, MDBennett E. Werner, MDFrom Cleveland Clinic Foundation, Cleveland, Ohio.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0048 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Packer and colleagues (1) raise unassailable points about the efficacy and cost-effectiveness of Entresto. I use the brand name because, as a newly released drug, the generic is not available and will not be for years. The answer to their question of why more physicians are not prescribing it is that it is too expensive. I have prescribed it many times only to receive a call from the pharmacy informing me that the patient learned the price and declined it.The problem is not that clinicians do not understand the benefits or that the accountants who calculate ...References1. Packer M, Armstrong WM, Rothstein JM, Emmett M. Sacubitril–valsartan in heart failure: why are more physicians not prescribing it?. Ann Intern Med. 2016;165:735-6. [PMID: 27571568]. doi:10.7326/M16-1932 LinkGoogle Scholar2. GoodRx. Prescription prices, coupons & pharmacy information. 2017. Accessed at www.goodrx.com on 23 March 2017. Google Scholar3. Global Care Rx. Canadian pharmacy online. 2017. Accessed at www.globalcarerx.com on 23 March 2017. Google Scholar Author, Article, and Disclosure InformationAffiliations: From Cleveland Clinic Foundation, Cleveland, Ohio.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0048. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSacubitril–Valsartan in Heart Failure: Why Are More Physicians Not Prescribing It? Milton Packer , W. Mark Armstrong , Joseph M. Rothstein , and Michael Emmett Sacubitril–Valsartan in Heart Failure Kevin E. Vitting Sacubitril–Valsartan in Heart Failure Brad Spellberg Sacubitril–Valsartan in Heart Failure Milton Packer , W. Mark Armstrong , Joseph M. Rothstein , and Michael Emmett Metrics 2 May 2017Volume 166, Issue 9Page: 680-681KeywordsConflicts of interestDisclosureDrugsHeart failure ePublished: 2 May 2017 Issue Published: 2 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...