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Post-remission strategies for patients with acute lymphoblastic leukemia (ALL) are limited to the multiagent chemotherapy and allogeneic stem cell transplant (allo-SCT), and cellular therapies are seldom involved. Although chemotherapy combined with mismatched granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell infusion (microtransplant, MST) has been studied in patients with acute myeloid leukemia, its efficacy in ALL is still undetermined. We enrolled 48 patients receiving hyper-CVAD-based MST between July 1, 2009, and January 31, 2018. No acute or chronic graft-versus-host disease occurred in patients receiving MST. Four-year overall survival (OS) and leukemia-free survival (LFS) were 62% and 35%, respectively, and the 4-year relapse rate was 65%. No patient experienced non–relapse mortality. Subgroup analysis showed that OS rates were comparable between groups with different age, risk stratification, minimal residual disease status prior to MST and immunophenotype. Adult patients tended to achieve better 4-year LFS (62% vs. 26%, P = .058) and lower hematologic relapse rate (38% vs. 74%, P = .058) compared with adolescent and young adult patients. Donor chimerism/microchimerism was detectable ranging from 0.002% to 42.78% in 78% (42/54) available samples within 14 days after each infusion and at 3 months or one year after the last cell infusion. Multivariate analyses demonstrated that white blood cells

Enzyme-catalysis self-assembled oligopeptide hydrogel holds great interest in drug delivery, which has merits of biocompatibility, biodegradability and mild gelation conditions. However, its application for protein delivery is greatly limited by inevitable degradation of enzyme on the encapsulated proteins leading to loss of protein activity. Moreover, for the intracellularly acted proteins, cell membrane as a primary barrier hinders the transmembrane delivery of proteins. The internalized proteins also suffer from acidic and enzymatic degradation in endosomes and lysosomes. We herein develop a protease-manipulated hybrid nanogel/nanofiber hydrogel for localized delivery of intracellularly acted proteins. The embedded polymeric nanogels (CytoC/aNGs) preserve activity of cytochrome c (CytoC) that is an intracellular activator for cell apoptosis as a model protein against proteolysis, and do not affect the gelation properties of the protease-catalysis assembled hydrogels. The injectable hydrogel (CytoC/aNGs/Gel) serves as a reservoir to enhance intratumoral retention and realize sustainable release of CytoC/aNGs. The released CytoC/aNGs increase cellular uptake of CytoC and enhance its intracellular delivery to its target site, cytoplasm, resulting in favorable apoptosis-inducing and cytotoxic effects. We show that a single local administration of CytoC/aNGs/Gel efficiently inhibit the tumor growth in the breast tumor mouse model., Graphical abstract A protease-manipulated hybrid nanogel/nanofiber hydrogel (CytoC/aNGs/Gel) was developed for localized delivery of an intracellularly-acted protein, cytochrome c (CytoC). A single local administration of CytoC/aNGs/Gel efficiently inhibited the tumor growth in breast tumor mouse model.Image 1

Persimmon tannin (PT) exhibits antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) isolated from retail pork. The involved molecular mechanisms were investigated for the first time using transcriptome and metabolome in this study. Results showed that subinhibitory concentration of PT (0.5 mg/ml) induced significant changes in MRSA at both transcriptional and metabolic levels, as 370 genes and 19 metabolites were differentially expressed. Bioinformatic analysis revealed that the varying genes and metabolites were mainly involved in pathways of membrane transport, amino acids, carbohydrate, and energy metabolism. The highlighted changes were those related to osmotic regulation, intracellular pH regulation, amino acid synthesis and metabolism, glycolysis, TCA cycle and iron metabolism, suggesting the multifaceted effects including cell membrane damage, amino acids limitation, energy metabolism disorder and iron deprivation induced by PT. The results provided insight into the anti-MRSA mechanism of PT, which is useful for PT’s development and application in food safety.

OBJECTIVE: To design a new extracorporeal reduction device for percutaneous pedicle screw fixation of thoracolumbar fractures (short for “new reduction device”), and to evaluate its effectiveness. METHODS: According to the mechanism of thoracolumbar fractures and biomechanics characteristic of reduction, a new reduction device was designed and used in a combination with long U-shaped hollow pedicle screw system. Between January 2014 and January 2016, 36 patients (group A) with single segment thoracolumbar fracture without neurological complications underwent percutaneous pedicle screw fixation, and the clinical data were compared with those of another 39 patients (group B) with thoracolumbar fracture underwent traditional open pedicle screw fixation. There was no significant difference in gender, age, cause of injury, classification of fractures, segments of fractures, injury to operation interval, height percentage of injury vertebrae, and kyphotic angle between 2 groups (P>0.05). The 2 groups were compared in terms of operation time, length of incision, intraoperative blood loss, drainage volume, visual analogue scale (VAS) at postoperative 24 hours, fluoroscopy frequency, ambulation time, height percentage of injury vertebrae, kyphotic angle and correction. RESULTS: Group A was significantly better than group B in the operation time, length of incision, intraoperative blood loss, drainage volume, VAS score at postoperative 24 hours, and ambulation time (P0.05). CONCLUSION: Minimally invasive extracorporeal reduction device for percutaneous pedicle screw fixation is an effective and safe treatment of thoracic vertebrae and lumbar vertebrae fractures, because of little trauma, less bleeding, and quicker recovery.

Celangulin V (CV) is the main insecticidal constituent of Celastrus angulatus. The V-ATPase H subunit of the midgut cells of lepidopteran larvae is the putative target protein of CV. Here, we compared the effects of CV on the midgut membrane potentials of Mythimna separata and Agrotis ipsilon larvae with those of the Cry1Ab toxin from Bacillus thuringiensis and with those of inactive CV-MIA, a synthetic derivative of CV. We investigated the changes in the apical membrane potentials (Vam) and basolateral membrane potentials (Vbm) of the midguts of sixth-instar larvae force-fed with the test toxins. We also measured the Vam and Vbm of larval midguts that were directly incubated with the test toxins. Similar to the effect of Cry1Ab, the Vam of CV-treated midguts rapidly decayed over time in a dose-dependent manner. By contrast, CV-MIA did not influence Vam. Meanwhile, the Vam of A. ipsilon larval midguts directly incubated with CV decayed less than that of M. separata larval midguts, whereas that of larvae force-fed with CV did not significantly change. Similar to Cry1Ab, CV did not affect the Vbm of isolated midguts. CV significantly inhibited V-ATPase activity in a dose-dependent manner. Therefore, CV initially inhibits V-ATPase in the apical membrane and affects intracellular pH, homeostasis, and nutrient transport mechanisms in lepidopteran midgut cells.

Periplocoside P (PSP), a novel compound isolated from Periploca sepium Bunge, possesses insecticidal activity against some lepidopterans, such as Mythimna separata. In M. separata, the brush border membrane vesicles of the midgut epithelium are the initial site of action of periplocosides. We conducted two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight/time of flight mass spectrometry analysis to analyze differentially expressed proteins (DEPs) from periplocoside P (PSP)-treated M. separata. We successfully isolated seven up-regulated and three down-regulated DEPs that have been previously identified, as well as a novel DEP. The DEPs are implicated in protein degradation, transporter, folding, and synthesis, and in juvenile hormone biosynthesis. DEPs involved in the oxidative phosphorylation energy metabolism pathway are enriched. Through real-time polymerase chain reaction assay, we confirmed that vma1 expression is significantly up-regulated expression levels in PSP-treated M. separata larvae. Enzymology validation further indicated that PSP can significantly inhibit V-type ATPase activity in a concentration-dependent manner. Given these results, we speculate that in M. separata, the V-type ATPase A subunit in the midgut epithelium is the putative target binding site of periplocosides. This finding provides preliminary evidence for the mode of action of periplocosides.

Periplocoside NW (PSNW) with pregnane glycoside skeleton is a novel insecticidal compound isolated from the root bark of Periploca sepium Bunge. This compound has a potent stomach poisoning activity against several insect pests. In this study, we observed the intoxication symptoms, investigated the histopathological effects and carried out immuno-electron microscopic localization of PSNW on the midgut epithelium of oriental armyworm Mythimna separata Walker larvae for better understanding its action mechanism against insects. Ultrastructural observations showed that cell damages caused by PSNW in the midgut of M. separata larvae are related to the degeneration of brush border microvilli. The dissolution of cytoskeletal structures in the interior and on the surface of microvilli was responsible for the decrease in size and eventual disappearance of microvilli when bubbles of cytoplasmic substances protrude into the midgut lumen of M. separata, thus resulting in cell death. The immuno-electron microscopic localization research showed that gold particle appeared on the microvilli layer of the midgut of M. separate larvae firstly. The density of gold particle gradually added with the time, and finally microvilli layer was destructed severely. Meantime, the gold particles were also presented to the intracellular organelle membrane and the organelles also were destructed. Therefore, we proposed that this membrane system on insect midgut epithelium cells is the initial acting site of PSNW against insects.

Periplocoside NW (PSNW) is a novel insecticidal compound isolated from the root bark of Periploca sepium Bunge and has potent stomach toxicity against some insect pests. Previous studies showed that the Mythimna separata larva is sensitive to PSNW, but the Agrotis ispilon larva is insensitive. In this study, preliminary target localization on the midgut of M. separata larvae was conducted via a fluorescence labeling technique. A comparative ultrastructural study on the effects of PSNW on the midguts of M. separata and A. ispilon larvae was performed. Symptom observation results showed that typical stomach toxicity was induced by PSNW in M. separata larvae. Fluorescence localization results showed that PSNW binds to the midgut cells of M. separata larvae. Ultrastructure observations showed destruction of the microvilli, organelle, and cytomembrane in the midgut cells of M. separata larvae, whereas no obvious changes were observed in midgut cells of A. ispilon larvae. These results were consistent with the insecticidal activity of PSNW. Therefore, PSNW might act on the midgut tissues of the insects, and one or more binding sites of PSNW may exist in M. separata larvae midgut cell cytomembranes.

Periplocosides, which are insecticidal compounds isolated from the root bark of Periploca sepium Bunge, can affect the digestive system of insects. However, the mechanism though which periplocosides induces a series of symptoms remains unknown. In this study, affinity chromatography was conducted by coupling periplocoside E-semi-succinic acid ester with epoxy amino hexyl (EAH) sepharose 4B. Sodium dodecyl sulfonate-polyacrylamide gelelectrophoresis (SDS-PAGE) was performed to analyze the fraction eluted by periplocoside E. Eight binding proteins (luciferin 4-monooxygenase, aminopeptidase N, aminopeptidase N3, nicotinamide adenine dinucleotide health (NADH) dehydrogenase subunit 5, phosphatidylinositol 3-phosphate 3-phosphatase myotubularin, actin, uncharacterized family 31 glucosidase KIAA1161, and 2OG-Fe(2) oxygenase superfamily protein) were obtained and identified through liquid chromatography/quadrupole-time of flight-mass spectrometry (LC/Q-TOF-MS) analysis of the midgut epithelium cells of Mythimna separata larvae. Aminopeptidase N and N3 are potential putative targets of periplocosides. This study establishes the foundation for further research on the mechanism of action and target localization of periplocosides in agricultural pests.

Preparation, detection, and quantification of CD19-directed chimeric antigen receptor-modified T (CAR-T) cells. (DOCX 17Â kb)

Preparation and quality control of mesenchymal stem cells (MSC). (DOCX 12Â kb)

Na(+)/K(+)-ATPase (sodium pump) is an important target for the development of botanical pesticide as it is responsible for transforming chemical energy in ATP to osmotic work and maintaining electrochemical Na(+ )and K(+ )gradients across the cell membrane of most animal cells. Celangulin IV (C-IV) and V (C-V), which are isolated from the root bark of Celastrus angulatus, are the major active ingredients of this insecticidal plant. The activities of C-IV and C-V on Na(+)/K(+)-ATPase were investigated by ultramicro measuring method to evaluate the effects of C-IV and C-V on Na(+)/K(+)-ATPase activities of the brain from the fifth Mythimna separata larvae and to discuss the insecticidal mechanism of C-IV and C-V. Results indicate that inhibitory activities of Na(+)/K(+)-ATPase by C-IV and C-V possess an obvious concentration-dependent in vitro. Compared with C-IV, the inhibition of C-V on Na(+)/K(+)-ATPase was not striking. In vivo, at a concentration of 25 mg/liter, the inhibition ratio of C-IV on Na(+)/K(+)-ATPase activity from the brain in narcosis and recovery period was more remarkable than that of C-V. Furthermore, the insects were fed with different mixture ratios of C-IV and C-V. The inhibition extent of Na(+)/K(+)-ATPase activity was corresponded with the dose of C-IV. However, C-V had no notable effects. This finding may mean that the mechanism of action of C-IV and C-V on Na(+)/K(+)-ATPase were different. Na(+)/K -ATPase may be an action target of C-IV and C-V.

Background Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. Case presentation We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Conclusions Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Trial registration Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550 Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0357-z) contains supplementary material, which is available to authorized users.