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PEG-interpenetrated dual-sensitive hydrogels that load nano lipid carrier (NLC) were researched and developed for topical drug administration. Natural antioxidant α-lipoic acid (ALA) was selected as our model drug. The α-lipoic acid (ALA) nano lipid carrier was successfully prepared by hot melt emulsification and ultrasonic dispersion method, and the physicochemical properties of the nano lipid carrier were investigated, including morphology, particle distribution, polydispersity coefficient, zeta potential and encapsulation efficiency. Carboxymethyl chitosan and poloxamer 407 contributed to pH- and temperature-sensitive properties in the hydrogel, respectively. Natural non-toxic cross-linking agent genipin reacted with carboxymethyl chitosan to form the hydrogel. Poly ethylene glycol (PEG), a polymer compound with good water solubility and biocompatibility, interpenetrated the hydrogel and influenced the mechanical strength and drug release behaviour. FI-IR test verified the successful synthesis of the hydrogel. The rheological parameters indicated that the mechanical strength of the hydrogel was positively correlated with the amount of PEG, and the in vitro dissolution profiles demonstrated that the increasement of PEG could accelerate the drug release rate. The compatibility of the drug delivery system was verified with cells and mice model. Topical delivery of ALA in solution, NLC and NLC-gel was investigated in-vitro.

Meta-analysis of 2 × 2 tables is common and useful in research topics including analysis of adverse events and survey research data. Fixed-effects inference typically centers on measures of association such as the Cochran-Mantel-Haenszel statistic or Woolf's estimator, but relies on assuming exact homogeneity across studies, which is often unrealistic. By showing that estimators of several widely-used methods have meaningful estimands even in the presence of heterogeneity, we derive improved confidence intervals for them under heterogeneity. These improvements over current methods are illustrated by simulation, and we also study which factors affect the coverage levels. We find that our confidence intervals provide coverage closer to the nominal level when heterogeneity is present, in both small and large-sample settings. The conventional confidence intervals derived under homogeneity are often conservative, though anti-conservative inferences occur in some scenarios. We also apply the proposed methods to a meta-analysis of 19 randomized clinical trials on the effect of sclerotherapy in preventing first bleeding for patients with cirrhosis and esophagogastric varices. Our methods provide a more interpretable approach to meta-analyzing binary data and more accuracy in characterizing the uncertainty of the estimators.

Semi-solid extrusion (SSE) 3D printing is an innovative and promising method that is suitable for the fabrication of personalized dosage forms of tablets. The aim of this study is to develop and evaluate the effectiveness of SSE 3D printed tablets with novel internal structures. Twelve types of 3D printed tablets with pre-designed structures were developed. Glipizide was selected as the model drug and three different concentrations of the HPMC K100LV polymer were used in the 3D printing process as the hydrophilic matrix. All of the printed tablets had satisfactory physical properties and structural integrity indicating the suitability of SSE 3D printing for the fabrication of personalized medicines with complex structures. The dissolution profiles of the printed tablets revealed the relationship between novel structures and drug release behavior. Tailored drug release may be easily achieved without changing the prescription by adjusting printing parameters such as outline value, grid width and printing pattern. All results of this paper clearly reveal the feasibility and capability of SSE 3D printing technology as a novel pharmaceutical manufacturing technique to fabricate personalized medicines and modulate drug dissolution profiles.

Full thickness cutaneous wound therapy and regeneration remains a critical challenge in clinical therapeutics. Recent reports have suggested that mesenchymal stem cells exosomes therapy is a promising technology with great potential to efficiently promote tissue regeneration. Multifunctional hydrogel composed of both synthetic materials and natural materials is an effective carrier for exosomes loading. Herein, we constructed a biodegradable, dual-sensitive hydrogel encapsulated human umbilical cord-mesenchymal stem cells (hUCMSCs) derived exosomes to facilitate wound healing and skin regeneration process. The materials characterization, exosomes identification, and in vivo full-thickness cutaneous wound healing effect of the hydrogels were performed and evaluated. The in vivo results demonstrated the exosomes loaded hydrogel had significantly improved wound closure, re-epithelialization rates, collagen deposition in the wound sites. More skin appendages were observed in exosomes loaded hydrogel treated wound, indicating the potential to achieve complete skin regeneration. This study provides a new access for complete cutaneous wound regeneration via a genipin crosslinked dual-sensitive hydrogel loading hUCMSCs derived exosomes.

Alpha-synuclein plays a vital role in the pathology of Parkinson's disease (PD). Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD.

Astrocytes are the most abundant glial cells in the central nervous system (CNS). As indispensable elements of the neurovascular unit, they are involved in the inflammatory response and disease-associated processes. Alpha-synuclein (α-syn) is released into the extracellular space by neurons and can be internalized by adjacent astrocytes, which activates glial cells to induce neuroinflammation. We were interested in whether astrocyte-mediated neuroinflammation is modulated by intracellular iron status and extracellular α-syn. Our results showed that recombinant α-syn (1 μg/ml and 5 μg/ml) treatment for 24 h did not affect the expression of the iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), nor those of iron regulatory protein (IRP) 1 or IRP2. Several proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 exhibited up-regulated mRNA levels in 5 μg/ml α-syn-treated astrocytes. TNF-α release was increased, indicating that inflammatory responses were triggered in these cells. Pretreatment with the iron-overload reagent ferric ammonium citrate (FAC, 100 μmol/L) for 24 h had no effects on mRNA levels and release of proinflammatory cytokines. Inflammatory responses triggered by α-syn were not affected by iron overload. The iron chelator desferrioxamine (DFO, 100 μmol/L) exerted suppressive effects on TNF-α mRNA levels, although no change was observed for TNF-α release. Hepcidin mRNA levels were down-regulated significantly in astrocytes co-treated with FAC and α-syn, although independent treatment with either FAC or α-syn did not alter hepcidin levels. In contrast, hepcidin mRNA levels were up-regulated in DFO and α-syn co-treated cells. As expected, ferritin protein levels were up-regulated or down-regulated with FAC or DFO treatment, respectively. Following the up-regulation of ferritin mediated by α-syn, hepcidin-to-ferritin levels were indicative of modulatory effects in α-syn-treated astrocytes with altered iron status. Therefore, we propose that the hepcidin-to-ferritin ratio is indicative of a detrimental response in primary cultured astrocytes experiencing iron and extracellular α-syn.

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8h floating process with traditional pharmaceutical excipients and lattice internal structure design.

Rationale The guidelines recommended gefitinib as a first-line targeted treatment for stage IV non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment for patients without T790m mutation. The case is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. Patient concerns We described a 55-year-old man with good performance status (PS). Diagnoses He was histopathologically diagnosed stage IV lung adenocarcinoma with EGFR mutations in November 2018. Interventions He was administrated with gefitinib daily (250 mg) for activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions,19del), and combined with platinum-based dual-drug chemotherapy. During the target treatments, the optimal efficacy evaluation was partial remission (PR) with a 12-month progression-free survival (PFS) time. Later, the intracranial progression of the patient rendered the treatment change to erlotinib. Outcomes It is surprising that the tumor lesion in brain as well as lung relieved obviously. His progression-free survival (PFS)was nearly 11 months, and the overall survival (OS)was>36 months up to now. The adverse events were tolerable. Lessions This case manifests that re-biopsy of advanced or recurrent NSCLC is beneficial to make a better therapeutic regimen, and erlotinib can be used as a salvage treatment after gefitinib failure.

The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol (PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in vitro dissolution condition, and we found the release profile fit Korsmeyer-Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations.

Small cell carcinoma of the bladder (SCCB) is a rare disease associated with high invasiveness and mortality. Histologically, SCCB is difficult to distinguish from small cell lung cancer (SCLC); however, it shares more similar molecular alterations with urothelial carcinoma (UC). As a result, now, the widely accepted theory about the cells of origin is that SCCB and UC probably have a common clone origin. Even the former probably comes from a preexisting UC. At present, given its rarity, early diagnoses, treatments, and follow-ups are not well established, which are vital to patients with SCCB. Inspirationally, in recent years, with the development of molecular diagnostic methods, molecular alterations of SCCB have been understood partially, which are propitious to excavate new potential therapeutic strategies and establish sound follow-ups. Therefore, the future will be light for patients with SCCB.

The objective of this study was to investigate the development of a novel puerarin gastric floating system with a concentric annular internal pattern by a 3D extrusion-based printing technique and to explore the flexibility of turning the release behavior through the design of the internal structure. The composition consisted of the conventional sustained-release pharmaceutical excipients without addition of foaming agent or light materials. First, the proper alcohol/water proportion was selected for the binding agent. The desired drug release behaviors and good floating properties were obtained either through modification of the formulation composition or adjustment of the internal structure. In vitro, the printed tablets were evaluated for drug release, mechanical properties, lag time, and floating duration time. The in vivo behaviors of the formulations were noted at certain time intervals through assessment of the radiographic pictures of healthy volunteers. The gastric retention time in the 3D-printed tablet was approximately 6 h in vivo. Results indicated these puerarin gastric floating 3D-printed tablets had great potential to achieve good gastric residence time and controlled release. Therefore, 3D extrusion-based printing appears to be appropriate for the production of oral administration systems, owing to its flexibility and the great floating ability and controlled-release capacity of its products.

In the present contribution, the aim is to explore and establish a way in which 3D printing and gastro-retentive drug delivery systems (GRDDSs) are combined (focusing on inner structure innovation) to achieve extended and stable gastro-retention and controlled-release of drug. Three digital models diverse in construction were designed and substantialized by a pressure-assisted microsyringe (PAM) 3D printer. Preparations were characterized by means of DSC, XRD, FTIR, and SEM. In vitro buoyancy study and in vivo gamma scintigraphy method were conducted to validate gastro-retention property of these innovative preparations in vitro/in vivo respectively. Release kinetic model was established and release mechanism was discussed. Tablets manufactured under certain range of parameters (intersecting angle, full filling gap) were tight and accurate in shape. Tablets printed with specific parameters (full filling gap, 50%; nozzle extrusion speed, 0.006 mm/s; layer height, 0.4 mm; compensation value, 0.25; quantity of layers, 15; outline printing value, 2) exhibited satisfactory in vitro (10-12 h)/in vivo (8-10 h) retention ability and possessed stable 10-12 h controlled-release quality. In general, 3D printing has tremendous advantage over conventional fabrication technique in intricate drug delivery systems and will be widely employed in pharmacy.

The expression level of tumor-related mRNA can reveal significant information about tumor progression and prognosis, so specific mRNA in cells provides an important approach for biological and disease studies. Here, fluorescence lifetime imaging of nanoflares in living cells was first employed to detect specific intracellular mRNA. We characterized the lifetime changes of the prepared nanoflares before and after the treatment of target mRNA and also compared the results with those of fluorescence intensity-based measurements both intracellularly and extracellularly. The nanoflares released the cy5-modified oligonucleotides and bound to the targets, resulting in a fluorescence lifetime lengthening. This work puts forward another dimension of detecting specific mRNA in cells and can also open new ways for detection of many other biomolecules.

Background Cancer initiation genes (CIGs) are genes that can directly promote cell proliferation or induce cancer. There are thousands of published studies identifying various CIGs; however, no systematic collection or description is available. Results To construct a CIG reference for genetic screening, we have collected 177 human genes curated from 1507 PubMed abstracts. To facilitate data queries and browsing, the identified CIGs along with extensive bioinformatic annotations were stored in an online database called CIGene. Initial functional analysis revealed an overlooked role for cell motility in cancer initiation. Subsequent cross-referencing of known tumor suppressor genes and oncogenes against the 177 CIGs identified 96 and 81 CIGs with and without known oncogenic roles, respectively. Successive network analyses of all 177 CIGs determined that the two groups of genes were more likely to link within their group. The distinct molecular functions for these groups were also confirmed with functional studies. While the 96 known oncogenic genes had fundamental roles in gene regulation and signaling, the remaining 81 genes possessed more ancillary functions, such enhancer binding. Further network and mutational analysis of the 96 known oncogenic genes revealed that mutations in these genes were highly prevalent in multiple cancers. By focusing on breast cancer, we found that 32 of the 96 genes with mutations in breast cancers were significantly associated with patient survival. Conclusions As the first literature-based online resource for CIGs, CIGene will serve as a useful gateway for the systematic analysis of cancer initiation. CIGene is freely available to all academic users at http://soft.bioinfo-minzhao.org/cigene/. Electronic supplementary material The online version of this article (10.1186/s12864-018-4944-y) contains supplementary material, which is available to authorized users.

Levetiracetam therapy is often associated with high levels of individual variation in the recommended dose required to achieve preferential treatment. Thus, a reliable and dynamic regulation system to accurately tailor dose is necessary. The main objective of this study is to explore and prepare a dose-flexible control system suitable for rapid release tablets equipped with high drug loading and a cylindrical model design. Semi-solid extrusion 3-dimensional printing was utilized to fabricate a series of tablets of increased volume. This method was compatible with 3 patterns to regulate the volumes to manipulate the tablet mass and achieve tailored personalized precision dosing. All tablets from each pattern exhibited a smooth surface and regular shape, as well as sufficient mechanical strength. A good linear correlation between the mass and theoretical volume of the tablets was maintained, regardless of the pattern used. The range of dose accuracy was between 103.3% and 96.2%, with an acceptable variation coefficient in the range of 0.6%-3.2%. Faster release behavior for levetiracetam can be achieved from the small-sized tablets due to their larger surface area/mass ratio. All the results demonstrated the potential and capability of semi-solid extrusion 3-dimensional printing as a novel pharmaceutical manufacturing technique to provide a dynamic and highly accurate controllable system for preparing patient-tailored medicines.

Background: Osmotic pump drug delivery systems are one of the most promising and widely developed systems. They are based on the principle of osmosis and are characterized by a zero-order release pattern independent of the physicochemical properties of the drug involved and some physiological factors. In the past 30 years, a series of difficulties, such as the very wide solubility range of different drugs, have been resolved accompanied by the development of various types of osmotic pumps. Furthermore, more advanced designs have been proposed according to practical requirements. Methods: We started a systematic references collection on osmotic pump systems through different available databases. Then these information were analyzed and divided according to different subjects. Finally, we made clear our thought and begun to write it in a logical way. Results: This review mainly concentrates on five kinds of functional osmotic pumps including technology combined, targeted, chronotherapy- based, ascending and compound osmotic pumps, involving ways to improve bioavailability and reduce side effects. Special attention is paid to the application of advanced imaging technologies to study osmotic pumps including the coating process, processing steps, polymer hydration and changes in the internal structure. Conclusions: Present-day osmotic pumps not only produce a constant release, but also have the ability to produce adjustable release according to practical requirements. Hence, technology combined, targeted, chronotherapy-based, ascending and compound osmotic pumps are a positive development. These latest advances offer various advantages compared with the classic osmotic pump, and enable them to meet the new needs for clinical use with fewer side effects and improved safety. In addition, following the improvements in the versatility and complexity of the novel osmotic pump system, conventional assessing parameters may fail to meet the increasing demand for information. Hence, novel imaging and monitoring technologies have been employed to monitor osmotic pumps from the coating process, processing steps, and polymer hydration to the changes in polymeric internal structure, which are associated with the different performance offered by the in vivo action of similar products.