Bio-Medical Science (South Korea)

Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.

Nanocellulose from various kinds of sources and nanocellulose-derived materials have been developed for electrochemical energy storage, including supercapacitors, lithium-ion batteries, lithium–sulfur batteries, and sodium-ion batteries.

HSC homing, quiescence, and self-renewal depend on the bone marrow HSC niche. A large proportion of solid tumor metastases are bone metastases, known to usurp HSC homing pathways to establish footholds in the bone marrow. However, it is not clear whether tumors target the HSC niche during metastasis. Here we have shown in a mouse model of metastasis that human prostate cancer (PCa) cells directly compete with HSCs for occupancy of the mouse HSC niche. Importantly, increasing the niche size promoted metastasis, whereas decreasing the niche size compromised dissemination. Furthermore, disseminated PCa cells could be mobilized out of the niche and back into the circulation using HSC mobilization protocols. Finally, once in the niche, tumor cells reduced HSC numbers by driving their terminal differentiation. These data provide what we believe to be the first evidence that the HSC niche serves as a direct target for PCa during dissemination and plays a central role in bone metastases. Our work may lead to better understanding of the molecular events involved in bone metastases and new therapeutic avenues for an incurable disease.

PURPOSE: Due to the potential risk of inducing cancer, radiation exposure by X-ray CT devices should be reduced for routine patient scanning. However, in low-dose X-ray CT, severe artifacts typically occur due to photon starvation, beam hardening, and other causes, all of which decrease the reliability of the diagnosis. Thus, a high-quality reconstruction method from low-dose X-ray CT data has become a major research topic in the CT community. Conventional model-based de-noising approaches are, however, computationally very expensive, and image-domain de-noising approaches cannot readily remove CT-specific noise patterns. To tackle these problems, we want to develop a new low-dose X-ray CT algorithm based on a deep-learning approach. METHOD: We propose an algorithm which uses a deep convolutional neural network (CNN) which is applied to the wavelet transform coefficients of low-dose CT images. More specifically, using a directional wavelet transform to extract the directional component of artifacts and exploit the intra- and inter- band correlations, our deep network can effectively suppress CT-specific noise. In addition, our CNN is designed with a residual learning architecture for faster network training and better performance. RESULTS: Experimental results confirm that the proposed algorithm effectively removes complex noise patterns from CT images derived from a reduced X-ray dose. In addition, we show that the wavelet-domain CNN is efficient when used to remove noise from low-dose CT compared to existing approaches. Our results were rigorously evaluated by several radiologists at the Mayo Clinic and won second place at the 2016 "Low-Dose CT Grand Challenge." CONCLUSIONS: To the best of our knowledge, this work is the first deep-learning architecture for low-dose CT reconstruction which has been rigorously evaluated and proven to be effective. In addition, the proposed algorithm, in contrast to existing model-based iterative reconstruction (MBIR) methods, has considerable potential to benefit from large data sets. Therefore, we believe that the proposed algorithm opens a new direction in the area of low-dose CT research.

As a promising two-dimensional (2D) conjugated polymer, polymeric carbon nitride (CN) is attracting dramatically increasing interest due to its unusual properties, facile synthesis from abundant and inexpensive starting materials, and promising applications ranging from (photo)catalysis, and photoelectrochemistry, to biosensors. The polymeric feature and facile synthesis of CN allow easy engineering of its structure at the molecular level. For instance, the moderate reactivity of CN at the interface, together with the aromatic π-conjugated framework and intralayer hydrogen bonds, provides ample possibilities to control its molecular structure and properties to meet task-specific applications. This review summarizes and highlights a panorama of the latest advancements related to the design and construction of the molecular structure of CN, such as by doping and copolymerization, engineering of the polymerization degree, coordination interaction, covalent and noncovalent functionalization, and modulation of intralayer hydrogen bonding. Beyond photocatalysis, the emerging applications of CN are also briefly discussed with a special emphasis on sensing, bioimaging and biotherapy, smart responsive systems and photoelectrochemical devices. This review ends with perspectives on the challenges and future prospects of molecular engineering of CN.

Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.

Abstract Laboratory experiments were conducted to examine the effect of charcoal addition on N2O emissions resulting from rewetting of air-dried soil. Rewetting the soil at 73% and 83% of the water-filled pore space (WFPS) caused a N2O emission peak 6 h after the rewetting, and the cumulative N2O emissions throughout the 120-h incubation period were 11 ± 1 and 13 ± 1 mg N m−2, respectively. However, rewetting at 64% WFPS did not cause detectable N2O emissions (−0.016 ± 0.082 mg N m−2), suggesting a severe sensitivity to soil moisture. When the soils were rewetted at 73% and 78% WFPS, the addition of charcoal to soil at 10 wt% supressed the N2O emissions by 89% . In contrast, the addition of the ash from the charcoal did not suppress the N2O emissions from soil rewetted at 73% WFPS. The addition of charcoal also significantly stimulated the N2O emissions from soil rewetted at 83% WFPS compared with the soil without charcoal addition (P < 0.01). Moreover, the addition of KCl and K2SO4 did not show a clear difference in the N2O emission pattern, although Cl− and SO2− 4, which were the major anions in the charcoal, had different effects on N2O-reducing activity. These results indicate that the suppression of N2O emissions by the addition of charcoal may not result in stimulation of the N2O-reducing activity in the soil because of changes in soil chemical properties.

Nowadays, diabetes mellitus has emerged as a significant global public health concern with a remarkable increase in its prevalence. This review article focuses on the definition of diabetes mellitus and its classification into different types, including type 1 diabetes (idiopathic and fulminant), type 2 diabetes, gestational diabetes, hybrid forms, slowly evolving immune-mediated diabetes, ketosis-prone type 2 diabetes, and other special types. Diagnostic criteria for diabetes mellitus are also discussed. The role of inflammation in both type 1 and type 2 diabetes is explored, along with the mediators and potential anti-inflammatory treatments. Furthermore, the involvement of various organs in diabetes mellitus is highlighted, such as the role of adipose tissue and obesity, gut microbiota, and pancreatic β-cells. The manifestation of pancreatic Langerhans β-cell islet inflammation, oxidative stress, and impaired insulin production and secretion are addressed. Additionally, the impact of diabetes mellitus on liver cirrhosis, acute kidney injury, immune system complications, and other diabetic complications like retinopathy and neuropathy is examined. Therefore, further research is required to enhance diagnosis, prevent chronic complications, and identify potential therapeutic targets for the management of diabetes mellitus and its associated dysfunctions.

Does the environment have a causal effect on economic development? Using meteorological data, we reconstruct every country's exposure to the universe of tropical cyclones during 1950-2008. We exploit random within-country year-to-year variation in cyclone strikes to identify the causal effect of environmental disasters on long-run growth. We compare each country's growth rate to itself in the years immediately before and after exposure, accounting for the distribution of cyclones in preceding years. The data reject hypotheses that disasters stimulate growth or that short-run losses disappear following migrations or transfers of wealth. Instead, we find robust evidence that national incomes decline, relative to their pre-disaster trend, and do not recover within twenty years. Both rich and poor countries exhibit this response, with losses magnified in countries with less historical cyclone experience. Income losses arise from a small but persistent suppression of annual growth rates spread across the fifteen years following disaster, generating large and significant cumulative effects: a 90th percentile event reduces per capita incomes by 7.4% two decades later, effectively undoing 3.7 years of average development. The gradual nature of these losses render them inconspicuous to a casual observer, however simulations indicate that they have dramatic influence over the long-run development of countries that are endowed with regular or continuous exposure to disaster. Linking these results to projections of future cyclone activity, we estimate that under conservative discounting assumptions the present discounted cost of "business as usual" climate change is roughly $9.7 trillion larger than previously thought.

The past decade has witnessed the emergence of carbon dots (c-dots), outshining other members of the carbon family because of their outstanding properties in fluorescence, cytocompatibility, photostability, electronic, mechanical and other chemical properties. This has resulted in an increasing number of applications in bioimaging, sensing, photovoltaic and medicine. Nature offers a wealth of exciting precursors that motivate constant persuasion of benign synthetic routes. Consequently, the past 5 years has seen a tremendous rise in green synthetic approaches of c-dots. This study reviews the journey of green c-dots by means of green sources of synthesis and their applications, with the major focus on various sensors and bioimaging probes.

There has been a tremendous amount of research in the past decade to optimize the mechanical properties and degradation behavior of the biodegradable Mg alloy for orthopedic implant. Despite the feasibility of degrading implant, the lack of fundamental understanding about biocompatibility and underlying bone formation mechanism is currently limiting the use in clinical applications. Herein, we report the result of long-term clinical study and systematic investigation of bone formation mechanism of the biodegradable Mg-5wt%Ca-1wt%Zn alloy implant through simultaneous observation of changes in element composition and crystallinity within degrading interface at hierarchical levels. Controlled degradation of Mg-5wt%Ca-1wt%Zn alloy results in the formation of biomimicking calcification matrix at the degrading interface to initiate the bone formation process. This process facilitates early bone healing and allows the complete replacement of biodegradable Mg implant by the new bone within 1 y of implantation, as demonstrated in 53 cases of successful long-term clinical study.

Photothermal therapy (PTT) has attracted extensive research attention as a noninvasive and selective treatment strategy for numerous cancers. PTT functions via photothermal effects induced by converting light energy into heat on near-infrared laser irradiation. Despite the great advances in PTT for cancer treatment, the photothermal therapeutics using laser devise only or non-specific small molecule PTT agents has been limited because of its low photothermal conversion efficiency, concerns about the biosafety of the photothermal agents, their low tumor accumulation, and a heat resistance of specific types of cancer. Using nanomaterials as PTT agents themselves, or for delivery of PTT agents, offers improved therapeutic outcomes with fewer side effects through enhanced photothermal conversion efficiency, accumulation of the PTT agent in the tumor tissue, and, by extension, through combination with other therapies. Herein, we review PTT's current clinical progress and present the future outlooks for clinical applications. To better understand clinical PTT applications, we describe nanomaterial-mediated photothermal effects and their mechanism of action in the tumor microenvironment. This review also summarizes recent studies of PTT alone or in combination with other therapies. Overall, innovative and strategically designed PTT platforms are promising next-generation noninvasive cancer treatments to move closer toward clinical applications.

Electrospinning has been used for the fabrication of extracellular matrix (ECM)-mimicking fibrous scaffolds for several decades. Electrospun fibrous scaffolds provide nanoscale/microscale fibrous structures with interconnecting pores, resembling natural ECM in tissues, and showing a high potential to facilitate the formation of artificial functional tissues. In this review, we summarize the fundamental principles of electrospinning processes for generating complex fibrous scaffold geometries that are similar in structural complexity to the ECM of living tissues. Moreover, several approaches for the formation of three-dimensional fibrous scaffolds arranged in hierarchical structures for tissue engineering are also presented.

Molecular design and recent progress on solution-processed TADF materials in OLEDs, including small molecules, polymers and dendrimers, is reviewed.

Objective To investigate the hypothesis that newly formed wound biofilms (or bioburdens) are more susceptible to antimicrobial treatment. Method Four separate and distinct models were performed by four separate biofilm research laboratories to evaluate the resistance of biofilms to antimicrobial treatments over time. These included a drip-flow biofilm model along with a hydrodebridement study, a porcine skin punch biopsy ex vivo model, a mouse chronic wound model and clinical longitudinal debridement study. Results All four models showed that, within the first 24 hours, the biofilm community was more susceptible to the selected antibiotics, and after maturing for up to 48 hours became increasingly tolerant. In each model, there was at least a 24-hour period in which the biofilms were more resistant to antibiotics. Each of the models utilised showed a significant decrease in the resistance of the biofilm/burden to gentamicin for up to 24 hours with a confidence interval of at least 95%. The resistance increased in each of the models by 48 hours and reached original resistance levels by 72 hours. Conclusion These data suggest the principles of biofilm-based wound care, along with the use of serial debridement to continually remove mature biofilm, followed by biofilm wound management strategies, including topical antibiotics while the bioburden is still immature and more susceptible, are valid. Conflict of interest SED is director of Research and Testing Laboratory, a commercial laboratory that develops molecular methods for diagnosis of wounds and infections and CEO of Pathogenius Laboratories, which is a molecular pathogen diagnostic company with a focus on chronic wounds. RDW is medical director of Southwest Regional Wound Care Center and inventor of biofilm-based wound care principles.

Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that Aβ interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.

High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well-known as the “good” cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and antioxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, and inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultrasmall size (8–12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12–24 h), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to those of endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize (a) clinical pharmacokinetics and safety of reconstituted HDL products, (b) comparison of HDL with inorganic and other organic nanoparticles, (c) the rationale for using HDL as drug delivery vehicles for important therapeutic indications, (d) the current state-of-the-art in HDL production, and (e) HDL-based drug delivery strategies for small molecules, peptides/proteins, nucleic acids, and imaging agents targeted to various organs.

SUMMARY: The human gingival niche is a unique microbial habitat. In this habitat, biofilm organisms exist in harmony, attached to either enamel or cemental surfaces of the tooth as well as to the crevicular epithelium, subjacent to a rich vascular plexus underneath. Due to this extraordinary anatomical juxtaposition, plaque biofilm bacteria have a ready portal of ingress into the systemic circulation in both health and disease. Yet the frequency, magnitude, and etiology of bacteremias due to oral origin and the consequent end organ infections are not clear and have not recently been evaluated. In this comprehensive review, we address the available literature on triggering events, incidence, and diversity of odontogenic bacteremias. The nature of the infective agents and end organ infections (other than endocarditis) is also described, with an emphasis on the challenge of establishing the link between odontogenic infections and related systemic, focal infections.

We have developed a microchip for polymerase chain reaction (PCR) with polydimethylsiloxane (PDMS). PDMS has good characteristics: it is cheap, transparent, easy to fabricate and biocompatible. But in micro PCR, the porosity of PDMS causes several critical problems such as bubble formation, sample evaporation and protein adsorption. To solve those problems, we coated the micro PCR chips with Parylene film, which has low permeability to moisture and long-term stability. We investigated the influence of low thermal conductivity of PDMS and Parylene on the thermal characteristics of the PCR chips with numerical analysis. The thermal responses of micro PCR chips were compared for three materials: silicon, glass and PDMS. From the results, we identified appropriate thermal responses of the PDMS-based micro PCR chips by heating both the top and bottom sides. We could successfully amplify the angiotensin converting enzyme gene with as small a volume as 2 μl on the PDMS-based micro PCR chips without any additives.

The origin and turnover of connective tissue cells in adult human organs, including the lung, are not well understood. Here, studies of cells derived from human lung allografts demonstrate the presence of a multipotent mesenchymal cell population, which is locally resident in the human adult lung and has extended life span in vivo. Examination of plastic-adherent cell populations in bronchoalveolar lavage samples obtained from 76 human lung transplant recipients revealed clonal proliferation of fibroblast-like cells in 62% (106 of 172) of samples. Immunophenotyping of these isolated cells demonstrated expression of vimentin and prolyl-4-hydroxylase, indicating a mesenchymal phenotype. Multiparametric flow cytometric analyses revealed expression of cell-surface proteins, CD73, CD90, and CD105, commonly found on mesenchymal stem cells (MSCs). Hematopoietic lineage markers CD14, CD34, and CD45 were absent. Multipotency of these cells was demonstrated by their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. Cytogenetic analysis of cells from 7 sex-mismatched lung transplant recipients harvested up to 11 years after transplant revealed that 97.2% +/- 2.1% expressed the sex genotype of the donor. The presence of MSCs of donor sex identity in lung allografts even years after transplantation provides what we believe to be the first evidence for connective tissue cell progenitors that reside locally within a postnatal, nonhematopoietic organ.