Potential Roles of Matrix Metalloproteinases in Malignant Mesothelioma

Malignant mesothelioma (MM) is a rare, aggressive, and highly lethal cancer that is primary induced by exposure to asbestos fibers. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in metastasis, and their overexpression correlates with tumor cell invasion and metastasis because they degrade the extracellular matrix (ECM) and process adhesion and cytoskeletal proteins, growth factors, chemokines, and cytokines. Recent evidence has shown that MMPs participate in MM progression, indicating that they are potential novel biomarkers and attractive targets for cancer therapy. In this chapter, we will describe MMPs in carcinogenic mechanisms based on in vivo and in vitro experimental evidence, outline the clinical findings, and speculate the possible roles of MMPs in MM

Temporal-Coded Deep Spiking Neural Network with Easy Training and Robust Performance

Spiking neural network (SNN) is interesting both theoretically and practically because of its strong bio-inspiration nature and potentially outstanding energy efficiency. Unfortunately, its development has fallen far behind the conventional deep neural network (DNN), mainly because of difficult training and lack of widely accepted hardware experiment platforms. In this paper, we show that a deep temporal-coded SNN can be trained easily and directly over the benchmark datasets CIFAR10 and ImageNet, with testing accuracy within 1% of the DNN of equivalent size and architecture. Training becomes similar to DNN thanks to the closed-form solution to the spiking waveform dynamics. Considering that SNNs should be implemented in practical neuromorphic hardwares, we train the deep SNN with weights quantized to 8, 4, 2 bits and with weights perturbed by random noise to demonstrate its robustness in practical applications. In addition, we develop a phase-domain signal processing circuit schematic to implement our spiking neuron with 90% gain of energy efficiency over existing work. This paper demonstrates that the temporal-coded deep SNN is feasible for applications with high performance and high energy efficient

The Role of Protein Arginine Methyltransferase 1 in Gastrointestinal Cancers

Mammals can produce nine kinds of arginine methylation enzymes that can be divided into three types (I, II, and III) according to their catalytic activity. Arginine methyltransferase 1 (PRMT1), as the first discovered arginine methyltransferase type I, has been reported to be involved in cell signal transduction, DNA damage repair, RNA transcription and other processes. Its imbalance or abnormal expression is also involved in cancer metastasis. PRMT1 is highly expressed in gastrointestinal tumors and promotes tumor biomarkers expression, chemotherapy resistance and tumorigenicity to promote cancer progression, while downregulation of PRMT1 expression can inhibit the migration and invasion of related tumor cells or promote tumor cells apoptosis and inhibit the progression of cancer. Therefore, PRMT1 may be a cancer therapeutic target. In this paper, arginine methylase 1 expression in various types of gastrointestinal tumors, the tumorigenic mechanism and the role of PRMT1 in tumorigenesis and development were reviewed

PPAR Ligands Function as Suppressors That Target Biological Actions of HMGB1

High mobility group box 1 (HMGB1), which has become one of the most intriguing molecules in inflammatory disorders and cancers and with which ligand-activated peroxisome proliferator-activated receptors (PPARs) are highly associated, is considered as a therapeutic target. Of particular interest is the fact that certain PPAR ligands have demonstrated their potent anti-inflammatory activities and potential anticancer effects. In this review article we summarize recent experimental evidence that PPAR ligands function as suppressors that target biological actions of HMGB1, including intracellular expression, receptor signaling cascades, and extracellular secretion of HMGB1 in cell lines and/or animal models. We also propose the possible mechanisms underlying PPAR involvement in inflammatory disorders and discuss the future therapeutic value of PPAR ligands targeting HMGB1 molecule for cancer prevention and treatment

p300/CBP Methylation is Involved in the Potential Carcinogenic Mechanism of Lung Cancer

p300/CBP is involved in the expression of a wide range of genes, both as a histone acetyltransferase (HAT) and as a coactivator of transcription factors. p300/CBP is the specific substrate of CARM1, and its KIX domain and GBD domain are the main sites methylated by arginine methyltransferase 4 (PRMT4/CARM1). p300/CBP plays an important role in lung cancer, which is a cell cycle disease. More importantly, the methylation of p300/CBP by CARM1 affects the progression of lung cancer through the cAMP-PKA pathway, p53 pathway and ER pathway. The structure, function, methylation modification sites, methylation-related enzymes, genes associated with lung cancer and the possible mechanisms of p300/CBP action are reviewed

HIV-1 variants with a single-point mutation in the gp41 pocket region exhibiting different susceptibility to HIV fusion inhibitors with pocket- or membrane-binding domain

AbstractEnfuvirtide (T20), the first FDA-approved peptide HIV fusion/entry inhibitor derived from the HIV-1 gp41 C-terminal heptad-repeat (CHR) domain, is believed to share a target with C34, another well-characterized CHR-peptide, by interacting with the gp41 N-terminal heptad-repeat (NHR) to form six-helix bundle core. However, our previous studies showed that T20 mainly interacts with the N-terminal region of the NHR (N-NHR) and lipid membranes, while C34 mainly binds to the NHR C-terminal pocket region. But so far, no one has shown that C34 can induce drug-resistance mutation in the gp41 pocket region. In this study, we constructed pseudoviruses in which the Ala at the position of 67 in the gp41 pocket region was substituted with Asp, Gly or Ser, respectively, and found that these mutations rendered the viruses highly resistant to C34, but sensitive to T20. The NHR-peptide N36 with mutations of A67 exhibited reduced anti-HIV-1 activity and decreased α-helicity. The stability of six-helix bundle formed by C34 and N36 with A67 mutations was significantly lower than that formed by C34 and N36 with wild-type sequence. The combination of C34 and T20 resulted in potent synergistic anti-HIV-1 effect against the viruses with mutations in either N- or C-terminal region in NHR. These results suggest that C34 with a pocket-binding domain and T20 containing the N-NHR- and membrane-binding domains inhibit HIV-1 fusion by interacting with different target sites and the combinatorial use of C34 and T20 is expected to be effective against HIV-1 variants resistant to HIV fusion inhibitors

Germline-Competent Mouse-Induced Pluripotent Stem Cell Lines Generated on Human Fibroblasts without Exogenous Leukemia Inhibitory Factor

Induced pluripotent stem (iPS) cells have attracted enormous attention due to their vast potential in regenerative medicine, pharmaceutical screening and basic research. Most prior established iPS cell lines were derived and maintained on mouse embryonic fibroblast (MEF) cells supplemented with exogenous leukemia inhibitory factor (LIF). Drawbacks of MEF cells impede optimization as well as dissection of reprogramming events and limit the usage of iPS cell derivatives in therapeutic applications. In this study, we develop a reproducible protocol for efficient reprogramming mouse neural progenitor cells (NPCs) on human foreskin fibroblast (HFF) cells via retroviral transfer of human transcriptional factors OCT4/SOX2/KLF4/C-MYC. Two independent iPS cell lines are derived without exogenous LIF. They display typical undifferentiated morphology and express pluripotency markers Oct4 and Sox2. Transgenes are inactivated and the endogenous Oct4 promoter is completely demethylated in the established iPS cell lines, indicating a fully reprogrammed state. Moreover, the iPS cells can spontaneously differentiate or be induced into various cell types of three embryonic germ layers in vitro and in vivo when they are injected into immunodeficient mice for teratoma formation. Importantly, iPS cells extensively integrate with various host tissues and contribute to the germline when injected into the blastocysts. Interestingly, these two iPS cell lines, while both pluripotent, exhibit distinctive differentiation tendencies towards different lineages. Taken together, the data describe the first genuine mouse iPS cell lines generated on human feeder cells without exogenous LIF, providing a reliable tool for understanding the molecular mechanisms of nuclear reprogramming

A Human Intestinal Infection Caused by a Novel Non-O1/O139 Vibrio cholerae Genotype and Its Dissemination Along the River

Non-O1/O139 Vibrio cholerae is increasingly reported in the clinical settings. However, intestinal infections via the consumption of non-O1/O139 V. cholerae-carrying seafood are rarely documented in China. In this study, we reported a case of mild watery diarrhea in a young male, caused by non-O1/O139 V. cholerae in the downstream of Liaohe River. Epidemiological investigation showed that this intestinal infection potentially associated with the raw consumption of mollusc. Prior to this finding, we conducted a 6-month pathogen surveillance of three locations along the Liaohe River and identified three environmental non-O1/O139 V. cholerae strains. To confirm the epidemiological links between clinical and environmental strains, high-resolution genomic typing was employed and revealed that V. cholerae isolated from human stool sample was genomically related to the one found in local mollusc and shared a common ancestor with other environmental strains obtained in the upstream sites of the Liaohe River. This fact suggests that the river is a natural reservoir for non-O1/O139 V. cholerae which poses a potential threat to the public health. In summary, our results deepened the insights on the transmission of non-pandemic V. cholerae strains and underscored the significance of genomic surveillance for drinking water along the river sites