Cytosolic Delivery of Thiolated Mn-cGAMP Nanovaccine to Enhance the Antitumor Immune Responses.

As a stimulator of interferon gene (STING), cyclic dinucleotide activates a broad cellular immune response for anti-cancer immunotherapy (CIT). However, the inherent of instability of 2' 3'-cyclic-GMP-AMP (cGAMP) with poor cellular targeting, rapid clearance, and inefficient transport to the cytoplasm seriously hinders cGAMP potency. Here, a thiolated and Mn2+ coordinated cyclic dinucleotide nanovaccine (termed as Mn-cGAMP NVs) to enable direct cytosolic co-delivery of cGAMP and Mn2+ to potentiate the antitumor immune response is presented. In the NVs, the fixation cGAMP with Mn2+ ions not only improve its stability, but also potentiate the activation of STING. Meanwhile, the presence of polysulfides on the NVs surface allowed direct cytosolic delivery while avoiding degradation. In this way, the production of cytokines for activating T cells immunity is greatly elevated, which in turn suppressed the primary and distal tumors growth through long-term immune memory and led to long-term survival of poorly immunogenic B16F10 melanoma mice. Moreover, by further combining with anti-PD-L1 monoclonal antibody, synergistic T cells antitumor immune response is elicited. This work offers a promising strategy to enhance the potency of cGAMP, holding a considerable potential for CIT applications.

Management of antibiotic-associated pseudomembranous colitis in Non-hospitalized and hospitalized patients.

Proper management of antibiotic-associated pseudo membranous colitis is not clear. This article is to investigate proper treatment of antibiotic-associated pseudo membranous colitis. Data of 67 patients (aged 18-69 years, with 31 males and 46 females) with antibiotic-associated pseudo membranous colitis were retrospectively analyzed including the demography, antibiotics to induce and for treatment of the pseudo membranous colitis, and other supportive measures. All 67 patients had a positive cytotoxin test, which confirmed the pseudo membranous colitis. Antibiotics which induced the pseudo membranous colitis included clindamycin, ofloxacin, piperacillin, cefatriaxone, penbritin and ceftazidime. Once the correct diagnosis was made, the culprit antibiotics were discontinued immediately, and narrow-spectrum antibiotics like metronidazole and vancomycin were administered in combination with correction of fluid and electrolyte abnormalities, use of vitamins C and B complex to repair the intestinal mucosa, and avoidance of antispasmodic and antidiarrheal agents. After appropriate treatment for 2-20 days, all patients recovered with no sequela. Sixty-two patients were clinically cured while five (7.5%) had diarrhea recurrence within two months of the end of therapy. Retreatment with tapering and extended period of metronidazole and/or vancomycin led to complete recovery of the patients. Multiple antibiotic agents are associated with pseudo membranous colitis, and correction of fluid and electrolyte abnormalities and use of vitamins to repair the intestinal mucosa should be performed to speed up the cure process.

Circular bivalent aptamers enhance the activation of the regenerative signaling pathway for repairing liver injury in vivo.

We developed a circular bivalent aptamer (CBA) to precisely activate membrane receptor-mediated regenerative signaling for liver repair in vivo. The CBA showed enhanced biostability and receptor binding avidity, achieving effective pathway activation and satisfactory treatment in an acetaminophen-induced liver injury model. This work expands aptamer-based molecular engineering in regenerative medicine.

3-D Deconvolutional Networks for the Unsupervised Representation Learning of Human Motions.

Data representation learning is one of the most important problems in machine learning. Unsupervised representation learning becomes meritorious as it has no necessity of label information with observed data. Due to the highly time-consuming learning of deep-learning models, there are many machine-learning models directly adapting well-trained deep models that are obtained in a supervised and end-to-end manner as feature abstractors to distinct problems. However, it is obvious that different machine-learning tasks require disparate representation of original input data. Taking human action recognition as an example, it is well known that human actions in a video sequence are 3-D signals containing both visual appearance and motion dynamics of humans and objects. Therefore, the data representation approaches with the capabilities to capture both spatial and temporal correlations in videos are meaningful. Most of the existing human motion recognition models build classifiers based on deep-learning structures such as deep convolutional networks. These models require a large quantity of training videos with annotations. Meanwhile, these supervised models cannot recognize samples from the distinct dataset without retraining. In this article, we propose a new 3-D deconvolutional network (3DDN) for representation learning of high-dimensional video data, in which the high-level features are obtained through the optimization approach. The proposed 3DDN decomposes the video frames into spatiotemporal features under a sparse constraint in an unsupervised way. In addition, it also can be regarded as a building block to develop deep architectures by stacking. The high-level representation of input sequential data can be used in multiple downstream machine-learning tasks, we evaluate the proposed 3DDN and its deep models in human action recognition. The experimental results from three datasets: 1) KTH data; 2) HMDB-51; and 3) UCF-101, demonstrate that the proposed 3DDN is an alternative approach to feedforward convolutional neural networks (CNNs), that attains comparable results.

Multiple roles of PPARalpha in brown adipose tissue under constitutive and cold conditions.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family, regulating fatty acid degradation in many organs. Two-dimensional SDS-PAGE of brown adipose tissue (BAT) from PPARalpha-null mice produced a higher-density spot. Proteomic analysis indicated that the protein was pyruvate dehydrogenase beta (PDHbeta). To observe PDHbeta regulation in BAT, the organ was stimulated by long-term cold exposure, and the activities of associated enzymes were investigated. Histological and biochemical analyses of BAT showed a significant decrease in the triglyceride content in wild-type mice and some degree of decrease in PPARalpha-null mice on cold exposure. Analyses of molecules related to glucose metabolism showed that the expression of PDHbeta is under PPARalpha-specific regulation, and that glucose degradation ability may decrease on cold exposure. In contrast, analyses of molecules related to fatty acid metabolism showed that numerous PPARalpha/gamma target molecules are induced on cold exposure, and that fatty acid degradation ability in wild-type mice is markedly enhanced and also increases to same degree in PPARalpha-null mice on cold exposure. Thus, this study proposes novel and multiple roles of PPARalpha in BAT.

Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy.

The binding between the immune checkpoints, programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1), compromises T-cell-mediated immune surveillance. Immune checkpoint therapy using immune checkpoint inhibitors (ICIs) to block PD-L1 on cancer cell membrane or PD-1 on activated T cell membrane can restore antitumor function of T cell. However, the intracellular expression of PD-L1 and its active redistribution to cancer cell membrane may impair the therapeutic benefits of ICIs. To address this issue, herein we develop a nanodrug (MS NPs) capable of reducing PD-L1 expression and enhancing antitumor effects. Methods: The nanodrug was self-assembled from immunoadjuvant metformin (Met, an old drug) and anticancer agent 7-ethyl-10-hydroxycamptothecin (SN38) via hydrogen bonds and electrostatic interactions. A series of experiments, including the characterization of MS NPs, the validation of MS NPs-mediated down-regulation of PD-L1 expression and in vitro therapeutic effect, the MS NPs-mediated in vivo chemo-immunotherapy and tumor metastasis inhibition were carried out. Results: Different from ICIs that conformationally block PD-L1 on cancer cell membrane, MS NPs directly reduced the PD-L1 level via metformin to achieve immunotherapy. Therefore, MS NPs showed enhanced chemo-immunotherapy effect than its counterparts. MS NPs were also effective in inhibiting tumor metastasis by remodeling the extracellular matrix and restoring immune surveillance. Additionally, no obvious toxicity was observed in major organs from MS NPs-treated mice and a high survival rate of mice was obtained after MS NPs treatment. Conclusion: We have designed nanodrug MS NPs by self-assembly of the immunoadjuvant Met and the anticancer agent SN38 for combined immunotherapy and chemotherapy. MS NPs might break the deadlock of antibody-based ICIs in immunotherapy, and repurposing old drug might provide a new perspective on the development of novel ICIs.

Correlation of the leucocyte count with traditional and non-traditional components of metabolic syndrome.

OBJECTIVES: To investigate correlation of the white blood cell (WBC) and its subtype count with the traditional and non-traditional components of the metabolic syndrome. METHODS: Between January 2012 and December 2013, 18,222 people were enrolled in this study. The height, weight, body mass index (BMI) and blood pressure were measured, and blood samples were tested for all subjects after an overnight fast. The count of WBC and its subtypes, total cholesterol, triglyceride, high density lipoprotein (HDL), low-density lipoprotein, aminotransferases, fibrinogen, uric acid, and fasting blood glucose were all assessed. RESULTS: Metabolic syndrome was found in 2502 of 18,222 healthy Chinese people (16.41%). The prevalence of metabolic syndrome was 22.61% for men significantly (P < 0.05) greater than for women (6.83%). The prevalence of obesity, hypertension, hyperglycemia and hyperlipidemia was significantly (P < 0.001) higher in people with than without metabolic syndrome. With increase of the WBC count, BMI, systolic and diastolic pressure, fasting blood glucose, triglyceride, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, glutamyltranspetidase, blood urea nitrogen fibrinogen and uric acid all went up significantly (P < 0.001) while HDL decreased significantly (P < 0.05). The creatinine remained relatively sTable After adjustment of age, sex, alcoholic drinking and education, the metabolic components of obesity, hypertension, diabetes and hyperlipidemia rose significantly (P < 0.05) positively with increased counts of the total WBC, neutrophil and lymphocyte, and the WBC and its subtypes were an independent risk factor for metabolic syndrome. CONCLUSION: Aminotransferases, fibrinogen and uric acid all significantly increase with increased WBC count in a dose-dependent manner. Increased counts of the total WBC and its subtypes are positively associated with presence of metabolic syndrome.

Suppression of expression of muscle-associated proteins by PPARalpha in brown adipose tissue.

Peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the steroid/nuclear receptor superfamily. Two-dimensional (2D) SDS-PAGE analysis of brown adipose tissue (BAT) unexpectedly revealed six spots that were present only in PPARalpha-null mice. Proteomic analysis indicated that these proteins were tropomyosin-1 alpha chain, tropomyosin beta chain, myosin regulatory light chain 2, myosin light chain 3, and parvalbumin alpha. Analyses of mRNA have revealed that PPARalpha suppressed the genes encoding these proteins in a synchronous manner in adult wild-type mice. Histological and physiological analyses of BAT showed in adult wild-type mice, a marked suppression of BAT growth concurrent with a prominent decrease in lipolytic and thermogenesis activities. These results suggest that in adult mice, PPARalpha functions to suppress the expression of the proteins that may be involved in the architecture of BAT, and thus may function in keeping BAT in a quiescent state.