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Divya Devadasan, Chiao-Wang Sun, Erik R Westin, Li-Chen Wu, Kevin M Pawlik, Tim M Townes, Frederick D Goldman
Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for patients with sickle cell disease (SCD). However, morbidity associated with myeloablative conditioning and graft versus host disease has limited its utility. To this end, autologous HSCT for SCD using lentiviral gene-modified bone marrow (BM) or peripheral blood stem cells has been undertaken, though toxicities of fully ablative conditioning with busulfan and incomplete engraftment have been encountered. Treosulfan, a busulfan analog with a low extra-medullary toxicity profile, has been employed successfully as part of a myeloablative conditioning regimen in the allogeneic setting in SCD...
April 20, 2018: Biology of Blood and Marrow Transplantation
Benjamin Schmuck, Mats Sandgren, Torleif Härd
Enzymatic functionalization of cross-β structured protein nanofibrils has hitherto resulted in a severe reduction of the catalytic efficiency of high turnover biocatalysts. It has been speculated that steric restrictions and mass transport pose limits on the attached enzymes, but detailed kinetics analyzing this have not yet been reported. For a more comprehensive understanding, we studied protein nanofibrils endowed with TEM1, a β-lactamase from Escherichia coli. The packing density of TEM1 along the fibrils was controlled by co-fibrillation; in other words, the N-terminal ureidosuccinate transporter Ure2(1-80) from Saccharomyces cerevisiae was simultaneously aggregated with the chimeric proteins TEM1-Ure2(1-80)...
2018: PloS One
Xue Chen, Ting Zhang, Hongyang Liu, Yaru Hao, Guoyang Liao, Xuemei Xu
Current available human papillomavirus (HPV) vaccines are based on the major capsid protein L1 virus-like particles (VLPs), which mainly induce type-specific neutralizing antibodies against vaccine types. Continuing to add more types of VLPs in a vaccine raises the complexity and cost of production which remains the principal impediment to achieve broad implementation of HPV vaccines, particularly in developing regions. In this study, we constructed 16L1-31L2 chimeric VLP (cVLP) by displaying HPV31 L2 aa.17-38 on the h4 coil surface region of HPV16 L1, and assessed its immunogenicity in mouse model...
April 23, 2018: Human Vaccines & Immunotherapeutics
Johannes Griss, Yasset Perez-Riverol, Matthew The, Lukas Käll, Juan A Vizcaíno
In the recent benchmarking article entitled "Comparison and Evaluation of Clustering Algorithms for Tandem Mass Spectra", Rieder et al. compared several different approaches to cluster MS/MS spectra. While we certainly recognize the value of the manuscript, here, we report some shortcomings detected in the original analyses. For most analyses, the authors only clustered single MS/MS runs. In one of the reported analyses, three MS/MS runs were processed together, which already led to computational performance issues in many of the tested approaches...
April 23, 2018: Journal of Proteome Research
A Khojasteh, S Hosseinpour, M M Dehghan, F Mashhadiabbas, M Rezai Rad, S Ansari, S Farzad Mohajeri, H H Zadeh
Among many applications of therapeutic monoclonal antibodies (mAbs), a unique approach for regenerative medicine has entailed antibody-mediated osseous regeneration (AMOR). In an effort to identify a clinically relevant model of craniofacial defect, the present study investigated the efficacy of mAb specific for bone morphogenetic protein- (BMP-) 2 to repair canine segmental mandibular continuity defect model. Accordingly, a 15 mm unilateral segmental defect was created in mandible and fixated with a titanium plate...
2018: BioMed Research International
Thitinee Vanichapol, Somchai Chutipongtanate, Usanarat Anurathapan, Suradej Hongeng
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function...
2018: BioMed Research International
Katsutomo Sasaki
Transcription factors play important roles not only in the development of floral organs but also in the formation of floral characteristics in various plant species. Therefore, transcription factors are reasonable targets for modifying these floral traits and generating new flower cultivars. However, it has been difficult to control the functions of transcription factors because most plant genes, including those encoding transcription factors, exhibit redundancy. In particular, it has been difficult to understand the functions of these redundant genes by genetic analysis...
January 2018: Breeding Science
Neil R Lloyd, Deborah S Wuttke
Pot1 is the shelterin component responsible for the protection of the single-stranded DNA (ssDNA) overhang at telomeres in nearly all eukaryotic organisms. The C-terminal domain of the DNA-binding domain, Pot1pC, exhibits non-specific ssDNA recognition, achieved through thermodynamically equivalent alternative binding conformations. Given this flexibility, it is unclear how specificity for ssDNA over RNA, an activity required for biological function, is achieved. Examination of the ribose-position specificity of Pot1pC shows that ssDNA specificity is additive but not uniformly distributed across the ligand...
April 18, 2018: Structure
Sandra Aguiar, Joana Dias, Ana M Manuel, Roberto Russo, Pedro M P Gois, Frederico A da Silva, Joao Goncalves
Antibody-drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue...
2018: Advances in Protein Chemistry and Structural Biology
Kai Han, Zhaoyu Ma, Xinxin Dai, Jin Zhang, Heyou Han
Tumor targeted drug delivery in vivo remains a significant challenge in tumor therapy. In this article, we fabricated a steric shielding protected/tumor acidity-activated chimeric peptide for tumor targeted photodynamic therapy. This amphiphilic chimeric peptide could form spherical nanoparticles at neutrally physiological environment with the shielding of biotin molecule (tumor target ligand). When in tumor acidic microenvironment, acidity-sensitive dimethylmaleic amide was rapidly hydrolyzed, resulting in subsequent liberation of (Lys)8 and the recovery of intramolecular electrostatic interaction between (Lys)8 and (Glu)8 ...
April 18, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Eloi R Verrier, Seung-Ae Yim, Laura Heydmann, Houssein El Saghire, Charlotte Bach, Vincent Turon-Lagot, Laurent Mailly, Sarah C Durand, Julie Lucifora, David Durantel, Patrick Pessaux, Nicolas Manel, Ivan Hirsch, Mirjam B Zeisel, Nathalie Pochet, Catherine Schuster, Thomas F Baumert
Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic GMP-AMP synthase (cGAS) was identified as a DNA sensor. In this study, we aimed to investigate the functional role of cGAS in sensing of HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss- and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes and HBV-infected human liver chimeric mice...
April 20, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Kenny Yu, A Saam Youshani, Fiona L Wilkinson, Claire O'Leary, Peter Cook, Liisi Laaniste, Aiyin Liao, Dominic Mosses, Christopher Waugh, Hannah Shorrock, Omar Pathmanaban, Andrew Macdonald, Ian Kamaly-Asl, Federico Roncaroli, Brian W Bigger
AIMS: Resident and peripherally-derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion, and attenuating host immune responses. Differentiating these cells' origins is challenging and current pre-clinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel non-myeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation...
April 20, 2018: Neuropathology and Applied Neurobiology
(no author information available yet)
Within the field of allogeneic chimeric antigen receptor T-cell therapy, La Jolla, CA-based Fate Therapeutics is exploring in vitro differentiation of induced pluripotent stem cells, rather than T cells harvested from donors, as their source material. Preclinical data on the company's off-the-shelf candidate, FT819, look promising so far.
April 20, 2018: Cancer Discovery
Yaru Yan, Xiaoqing Liu, Qingbin Li, Xiaoyu Chu, Jian Tian, Ningfeng Wu
In the previous study, the results on two interesting egfp genes indicated that the expressed eGFP production of egfp-codon containing multiple rare codons was 2.3-fold than that of egfp-genscript with mainly high-frequency-usage codons. Therefore, the rare codons also play important roles for the functional expression of genes and it is interesting to know which rare codons in the egfp affect the functional expression of eGFP. In this study, the structure-guided SCHEMA recombination method and site-specific mutagenesis were proposed to detect the contribution of the rare codons on the functional expression of eGFP...
April 17, 2018: Protein Expression and Purification
Eric L Smith, Mette Staehr, Reed Masakayan, Ishan J Tatake, Terence J Purdon, Xiuyan Wang, Pei Wang, Hong Liu, Yiyang Xu, Sarah C Garrett-Thomson, Steven C Almo, Isabelle Riviere, Cheng Liu, Renier J Brentjens
B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered...
March 28, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Isabelle Dierckx de Casterlé, An D Billiau, Ben Sprangers
Allogeneic hematopoietic stem cell transplantation (alloHSCT) produces -similar to the long-established graft-versus-leukemia effect- graft-versus-solid-tumor effects. Clinical trials reported response rates of up to 53%, occurring mostly but not invariably in association with full donor chimerism and/or graft-versus-host disease. Although donor-derived T cells are considered the principal effectors of anti-tumor immunity after alloHSCT or donor leukocyte infusion (DLI), growing evidence indicate that recipient-derived immune cells may also contribute...
April 12, 2018: Blood Reviews
Naoki Takaoka, Seigo Sanoh, Katsuhiro Okuda, Yaichiro Kotake, Go Sugahara, Ami Yanagi, Yuji Ishida, Chise Tateno, Yoshitaka Tayama, Kazumi Sugihara, Shigeyuki Kitamura, Mami Kurosaki, Mineko Terao, Enrico Garattini, Shigeru Ohta
As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O6 -benzylguanine as substrates...
April 17, 2018: Biochemical Pharmacology
Sarah J Rosen, Paul E Harris, Mark A Hardy
Despite decades of research, the induction and maintenance of long-term allograft tolerance without immunosuppression remains an elusive goal in the field of solid organ and cell transplantation. Immunosuppressive medications frequently prevent or minimize acute cellular rejection but have failed to halt anti-donor antibody production and chronic organ rejection. Past efforts aimed at promoting lasting allograft tolerance have focused primarily on peripheral T cell depletion, augmentation of regulatory T cells, or induction via simultaneous hematopoietic stem cell transplantation and facilitation of donor chimerism...
April 19, 2018: Transplantation
Jared P Mohr, Poorna Perumalla, Juan D Chavez, Jimmy K Eng, James E Bruce
Chemical cross-linking combined with mass spectrometry provides a method to study protein structures and interactions. The introduction of cleavable bonds in a cross-linker provides an avenue to decouple released peptide masses from their precursor species, greatly simplifying the downstream search, allowing for whole proteome investigations to be performed. Typically, these experiments have been challenging to carry out, often utilizing non-standard methods to fully identify cross-linked peptides. Mango is an open source software tool that extracts precursor masses from chimeric spectra generated using cleavable cross-linkers, greatly simplifying the downstream search...
April 20, 2018: Analytical Chemistry
Feng Li, Tengfei Zhang, Ling Cao, Yi Zhang
Cancer immunotherapy, a new weapon against cancers by harnessing the patient's own immune system, potentiates an extended remission and possibly a cure for cancer. T cells genetically engineered with chimeric antigen receptor (CAR) vectors can specifically target the surface antigen of cancer cells and kill them in an MHC-independent manner. CD19 is extensively expressed on cancerous cells in B cell malignancies. To target this antigen, CAR T cells have gained great success in treating patients with B cell leukemia and lymphoma...
April 19, 2018: Current Stem Cell Research & Therapy
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