A Homozygotic Mutation in KDSR may Cause Keratinization Disorders and Thrombocytopenia: A Case Report.

Pathogenic mutations in 3-keto-dihydrosphingosine reductase (KDSR) gene are associated with keratinization disorders and impaired platelet function. However, no case with both homozygotic mutation of KDSR and hepatic hemangioendothelioma has ever been reported due to its low prevalence. Here we report a seven months old Chinese boy with a homozygotic missense mutation in KDSR and both of his parents carry a same heterozygous mutation. He was born with thick plate-like scales overlying erythrodermic skin, but the skin symptoms were resolved spontaneously over the first month of his birth. He was also diagnosed with hepatic hemangioendothelioma at birth and accepted a resection surgery at 2 months old. At birth, his platelet count was severely low (10-20×109/L) with recurrent skin and gingival bleeding. Meanwhile, he suffered a mild normocytic, normochromic anemia with normal iron and hematinic levels. The anemia spontaneously recovered over the first 6 months, while the platelet count keeped at a low level (4-20×109/L). Treatment with corticosteroids, immunoglobulin or thrombopoietin was all suboptimal.

Mechanical and Morphological Analysis of Cancer Cells on Nanostructured Substrates.

Cancer metastasis is a major cause of cancer-induced deaths in patients. Mimicking nanostructures of an extracellular matrix surrounding cancer cells can provide useful clues for metastasis. This paper compares the morphology, proliferation, spreading, and stiffness of highly aggressive glioblastoma multiforme cancer cells and normal fibroblast cells seeded on a variety of ordered polymeric nanostructures (nanopillars and nanochannels). Both cell lines survive and proliferate on the nanostructured surface and show more similarity on nanostructured surfaces than on flat surfaces. Although both show similar stiffness on the nanochannel surface, glioblastomas are softer, spread to a larger area, and elongate less than fibroblasts. The nanostructured surfaces are useful for in vitro model of an extracellular matrix to study the cancer cell migratory phenotype.

Radiotherapy and PGEMOX/GELOX regimen improved prognosis in elderly patients with early-stage extranodal NK/T-cell lymphoma.

The optimal treatment strategy for elderly patients with natural killer/T-cell lymphoma (NKTCL) remains to be established. A total of 63 elderly patients with newly diagnosed NKTCL were retrospectively reviewed. Among the patients with stage I-II disease, 58.3 % received radiotherapy (RT) ± chemotherapy, and 41.7 % received chemotherapy alone. Compared with chemotherapy alone, RT ± chemotherapy elicited a significantly higher overall response rate (ORR) (100 vs. 57.1 %, P < 0.001) and substantially prolonged 5-year overall survival (OS) (55.3 vs. 18.0 %, P < 0.001) in patients with stage I-II disease. Compared with other chemotherapeutic regimens, pegaspargase plus gemcitabine and oxaliplatin (PGEMOX)/L-asparaginase plus gemcitabine and oxaliplatin (GELOX) was associated with a significantly higher ORR (92.9 vs. 51.6 %, P = 0.009) and a significantly improved 5-year OS (78.6 vs. 23.9 %, P = 0.010) in patients with stage I-II disease. Nine patients with stage I-II disease who were treated with PGEMOX/GELOX followed by RT had an encouraging outcome (5-year OS 100 %, 5-year progression-free survival (PFS) 85.7 %), which was superior to that of patients receiving other regimens followed by RT. In conclusion, RT played an important role for elderly patients with early-stage NKTCL, and the PGEMOX/GELOX regimen was superior to other regimens. The combination of them may be a promising treatment option.

Bilayer metallic nanofilms as broadband antireflection coatings in terahertz optical systems.

We present the potential of ultrathin bilayer metallic nanofilms for use as broadband antireflection coatings in the terahertz frequency range. The metallic layers are modeled using a wave-impedance matching approach. The experimental and theoretical results are in good agreement. Further, a novel method using our broadband antireflection coatings is proposed to eliminate unwanted reflections that interfere with the important reflection from the sample in terahertz reflection measurement. The proposed method significantly improves the calculation of the optical properties of liquid and biological samples.

Polyelectrolyte properties of filamentous biopolymers and their consequences in biological fluids.

Anionic polyelectrolyte filaments are common in biological cells. DNA, RNA, the cytoskeletal filaments F-actin, microtubules, and intermediate filaments, and polysaccharides such as hyaluronan that form the pericellular matrix all have large net negative charge densities distributed over their surfaces. Several filamentous viruses with diameters and stiffnesses similar to those of cytoskeletal polymers also have similar negative charge densities. Extracellular protein filaments such collagen, fibrin and elastin, in contrast, have notably smaller charge densities and do not behave as highly charged polyelectrolytes in solution. This review summarizes data that demonstrate generic counterion-mediated effects on four structurally unrelated biopolymers of similar charge density: F-actin, vimentin, Pf1 virus, and DNA, and explores the possible biological and pathophysiological consequences of the polyelectrolyte properties of biological filaments.

Thermal preparation of lysozyme-imprinted microspheres by using ionic liquid as a stabilizer.

Thermal preparation of lysozyme-imprinted microspheres was firstly investigated by using biocompatible ionic liquid (IL) as a thermal stabilizer. The imprinted microspheres made with IL could obtain the good recognition ability to template protein, whereas the imprinted polymer synthesized in the absence of it had a similar adsorption capacity to the non-imprinted one. Furthermore, the preparation conditions of imprinted polymers (MIPs) including the content of IL, temperature of polymerization, and types of functional monomers and crosslinkers were systematically analyzed via circular dichroism spectrum and activity assay. The results illustrated that using hydroxyethyl acrylate as the functional monomer, ethylene glycol dimethacrylate as the crosslinker, 5 % IL as the stabilizer, and 75 °C as the reaction temperature could retain the structure of template protein as much as possible. The obtained MIPs showed excellent recognition ability to the template protein with the separation factor and selectivity factor value of 4.30 and 2.21, respectively. Consequently, it is an effective way to accurately imprint and separate template protein by cooperatively using circular dichroism spectroscopy and activity assay during the preparation of protein MIPs. The method of utilizing IL to stabilizing protein at high temperature would offer a good opportunity for various technologies to improve the development of macromolecules imprinting.

Effects of non-linearity on cell-ECM interactions.

Filamentous biopolymers such as F-actin, vimentin, fibrin and collagen that form networks within the cytoskeleton or the extracellular matrix have unusual rheological properties not present in most synthetic soft materials that are used as cell substrates or scaffolds for tissue engineering. Gels formed by purified filamentous biopolymers are often strain stiffening, with an elastic modulus that can increase an order of magnitude at moderate strains that are relevant to cell and tissue deformation in vivo. This review summarizes some experimental studies of non-linear rheology in biopolymer gels, discusses possible molecular mechanisms that account for strain stiffening, and explores the possible relevance of non-linear rheology to the interactions between cell and extracellular matrices.

Vicious Cycle-Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis.

During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.

Coagulation/co-catalytic membrane integrated system for fouling-resistant and efficient water purification.

Low-pressure catalytic membranes allow efficient rejection of particulates and simultaneously removing organics pollutant in water, but the accumulation of dissolved organic matters (DOM) on membrane surface, which cover the catalytic sites and cause membrane fouling, challenges their stable operation in practical wastewater treatment. Here we propose a ferric salt-based coagulation/co-catalytic membrane integrated system that can effectively mitigate the detrimental effects of DOM. Ferric salt (Fe3+) serving both as a DOM coagulant to lower the membrane fouling and as a co-catalyst with the membrane-embedded MoS2 nanosheets to drive perxymonosulfate (PMS) activation and pollutant degradation. The membrane functionalized with 2H-phased MoS2 nanosheets showed improved hydrophilicity and fouling resistance relative to the blank polysulfone membrane. Attributed to the DOM coagulation and co-catalytic generation of surface-bound radicals for decontamination at membrane surface, the catalytic membrane/PMS/ Fe3+ system showed much less membrane fouling and 2.6 times higher pollutant degradation rate in wastewater treatment than the catalytic membrane alone. Our work imply a great potential of coagulation/co-catalytic membrane integrated system for water purification application.

Long-term stability of pleural fluid carcinoembryonic antigen and its effect on the diagnostic accuracy for malignant pleural effusion.

BACKGROUND: The in vitro stability assessment is essential for investigating the diagnostic accuracy of pleural biomarkers. This study aimed to investigate the long-term stability of pleural fluid carcinoembryonic antigen (CEA) at -80°C to -70°C. In addition, we analyzed the effects of frozen storage on the diagnostic accuracy of CEA for malignant pleural effusion (MPE). METHODS: Pleural fluid CEA of participants in two prospective cohorts were stored at -80°C to -70°C for 1-3 years. The CEA level in the stored specimen was measured with an immunoassay, and its level in the fresh specimen was extracted from medical records. The Bland-Altman method, Passing-Bablok regression, and Deming regression were used to analyze the agreement of CEA between the fresh and frozen pleural fluid. In addition, we used receiver operating characteristic (ROC) curves to evaluate the diagnostic accuracy of CEA in the fresh and frozen specimens for MPE. RESULTS: A total of 210 participants were enrolled. The median CEA levels in frozen and fresh pleural fluid specimens were similar (frozen, 2.32 ng/mL; fresh, 2.59 ng/mL; p < 0.01). The slopes and intercepts in the Passing-Bablok regression (intercept 0.01, slope 1.04) and Deming regression (intercept 0.65; slope 1.00) were not statistically significant (p > 0.05 for all). No significant difference was observed between the area under the ROC curves of CEA in the fresh and frozen specimens (p > 0.05 for all). CONCLUSION: Pleural fluid CEA is seemingly stable when stored at -80°C to -70°C for 1-3 years. Frozen storage does not significantly affect the diagnostic accuracy of CEA for MPE.

Genome sequencing identified a novel exonic microdeletion in the RUNX2 gene that causes cleidocranial dysplasia.

BACKGROUND AND AIMS: Cleidocranial dysplasia (CCD) represents a rare autosomal dominant skeletal dysplasia caused by mutations that induce haploinsufficiency in RUNX2, the important transcription factor of osteoblasts related to bone/cartilage development and maintenance. Clavicular hypoplasia, which involves aberrant tooth/craniofacial bone/skeletal formation, is a feature of classic CCD. RUNX2 mutations can be found in approximately 60-70% of patients with CCD, and around ∼10% of these mutations are microdeletions. The present paper describes the radiological and clinical characteristics of a 5-year-old girl who showed representative CCD features, including extra teeth, aplasia of clavicles, sloping shoulders, marked calvarial hypomineralization, and osteoporosis. MATERIALS AND METHODS: We obtained genomic DNA of her family members and performed whole-genome sequencing (WGS) for samples collected from the proband. Quantitative fluorescent PCR (QF-PCR) and specific PCR plus electrophoresis were then performed as validation assays for all participants. In vitro analysis was performed. Luciferase assay for Runx2 transcription activity and evaluation of mRNA levels of Runx2 downstream osteogenic markers were conducted. RESULTS: WGS identified a 11.38-kb microdeletion in RUNX2 comprising 8-9 exons, which was validated by QF-PCR and specific PCR plus electrophoresis. In vitro experiments confirmed the pathogenicity of this variation. CONCLUSION: The present study identified a 11.38-kb microdeletion in RUNX2 that causes CCD. The deletion in the PST domain of RUNX2 reduces its transcription activity and reduces osteogenic marker levels, eventually decreasing the differentiation of osteoblasts. These findings clarify the role of the CCD-related mechanism in the development of CCD and suggest that it is important to consider copy number variation for the suspected familial patients early.

Wettability, surface microstructure and mechanical properties of films based on phosphorus oxychloride-treated zein.

BACKGROUND: Zein, the predominant protein in corn, has been extensively studied as an alternative packaging material in edible and biodegradable films. However, films made from 100% zein are brittle under normal conditions. The aim of this investigation was to improve the film-forming properties of zein by chemical phosphorylation. The surface hydrophobicity, surface microstructure and mechanical properties of films based on untreated and phosphorus oxychloride (POCl(3))-treated zein were evaluated and compared. The effect of POCl(3) treatment on the rheological properties of zein solutions was also studied. RESULTS: POCl(3) treatment, especially at pH 7 and 9, led to an increase in the apparent viscosity of zein solutions. Atomic force microscopy (AFM) analysis showed that the film based on POCl(3) -treated zein at pH 7 had a stone-like surface microstructure with a higher roughness (R(q)) than the untreated zein film. The AFM data may partially account for the phenomenon that this film exhibited high surface hydrophobicity (H(0) ). POCl(3) treatment diminished the tensile strength (TS) of zein films from 4.83-6.67 to 1.3-2.29 MPa. However, the elongation at break (EAB) of the films at pH 7 and 9 increased from 3.0-4.5% (control film) to 150.1-122.7% (POCl(3) -treated film), indicating the potential application of zein films in wrapping foods or in non-food industries such as sugar, fruit or troche that need good extension packing materials. CONCLUSION: The data presented suggest that the properties of zein films could be modulated by chemical phosphorylation treatment with POCl(3) at an appropriate pH value.

Periodontal treatment of furcation involvement at the mandibular first molar with a follow-up of 27 years.

Due to the complicated anatomical structures in the furcation area of multirooted mandibular first molars, dental hygiene is greatly compromised once the furcation is involved in the periodontitis, leading to the unfavorable prognosis of teeth with furcation involvement. A patient came to a dental office with the chief complaint of "mobile mandibular posterior tooth" 27 years ago. The periapical film showed alveolar bone resorption at the root furcation of the right mandibular first molar. Flap surgery and fine supportive therapy were conducted. The patient was diagnosed with "furcation involvement Class Ⅲ" during a revisit three years ago. Satisfactory and healthy periodontal statuses were observed 2, 9, 24, and 33 months after the periodontal flap surgery plus tunneling procedures. A follow-up of 27 years in the present case demonstrated that a favorable prognosis of furcation involvement can be achieved after adequate periodontal treatment.

[Biodegradation of Polystyrene by Geobacillus stearothermophilus].

Biodegradation is the most sustainable treatment method for waste polystyrene (PS). Thermophiles possess highly efficient biotransformation capabilities that could enhance the biodegradation efficiency of organic solid wastes. However, detailed research on the degradation of PS plastics by thermophile is scarce. Here, the degradation performance of a strain of Geobacillus stearothermophilus FAFU011 (FAFUA011) isolated from compost was examined. The results showed that strain FAFUA011 could utilize PS as the sole carbon source for growth and formed a stable biofilm on the surface of PS fragments. During 56 days of degradation, FAFU0011 caused a total mass loss of PS of 4.2% and decrease in molecular weight of 17.4%-18.2%. Based on SEM observations, FAFUA011 causes erosion hollows on the surface of PS, thus increasing the type and number of oxygen-containing structures that alter its hydrophilic properties. These changes facilitate the colonization of other microorganisms and further promote biodegradation. Based on 2D-COS analysis, the chronological order of the change in functional groups during the degradation process were identified as follows:1491 cm-1(C-H) > 1450 cm-1(C-H) > 1601 cm-1(C=C) > 1027 cm-1(C-O) > 1068 cm-1(C=O) > 1366 cm-1(C-OH). Overall, these results reveal that FAFU011 could promote the thermophilic bio-oxidative degradation of PS plastic.

Metabolic and biophysical study of the MFN2Ile213Thr mutant causing Hereditary Motor and Sensory Neuropathy (HMSN).

Charcot-Marie-Tooth (CMT) 2A disease, a genetic axonal nervous lesion, results from MFN2 pathogenic variation, and this gene plays a pivotal role in mitochondrial dynamics and calcium signaling. However, the underlying mechanism linking MFN2 defect to progressive dying-back of peripheral nerves is still unclear. The present work focused on analyzing one CMT2A patient from multiple perspectives. Clinical and pathologic evaluation was initially conducted on the recruited case. Subsequently, Sanger sequencing and whole-exome sequencing (WES) were performed for genetic detection. To reveal the cell metabolic alteration caused by the identified variant, this study also established and transfected plasmid vectors in HEK293 cells and analyzed cell metabolites through liquid chromatography in combination with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS). Additionally, we completed structural modeling and molecular dynamic (MD) simulation to investigate the intramolecular impact of the variant. According to our results, the clinical and neuropathologic manifestations of the proband matched with the diagnosis of CMT. The causative variant MFN2: c.638T>C: (p.Ile213Thr) was identified through genetic analysis. Moreover, metabolic pathway enrichment results demonstrated that this variant significantly affected the metabolism of sphingolipids and glycerophospholipids. MD analysis indicated that this variant crippled the binding ability of MFN2 to GTP. Taken together, our study deduced preliminary clues for the underlying mechanism by which mutant MFN2 affects cell metabolism and provided a novel perspective to understand the cellular and molecular impacts of MFN2 variants.

Batch fabrication of electrochemical sensors on a glycol-modified polyethylene terephthalate-based microfluidic device.

Developing low-cost methods for the fabrication of electrochemical microfluidic devices is urgently needed for transferring such devices from fundamental research to daily-life technology. Herein, glycol-modified polyethylene terephthalate (PETG)-based microfluidic devices with embedded channels and gold film electrode (GFE) are developed by a one-step, low-cost, straightforward, and mass-producible method, and are sealed by a reversible hydrophilic tape-based mechanism. Easily accessible poly (methyl methacrylate) (PMMA), polyethylene terephthalate (polyester, PET), and PETG are explored as substrate options for fabricating electrochemical sensors. The results demonstrated that PETG can be an excellent substrate for fabricating the electrode. The electrochemical stability and morphology of the device are investigated. Both redox ions ([Fe(CN)6]3-/4-) and redox organic compounds (dopamine) are used as model analytes to prove the electrochemical performance of the device. The PETG-based microfluidic devices integrated with electrochemical sensors can be used as alternative electrochemical devices for the detection of biological and chemical analytes. Meanwhile, batch-fabricated flexible electrochemical sensors based on PETG film and their electrochemical performance are reported.

Nonlinear elasticity of stiff filament networks: strain stiffening, negative normal stress, and filament alignment in fibrin gels.

Many biomaterials formed by cross-linked semiflexible or rigid filaments exhibit nonlinear theology in the form of strain-stiffening and negative normal stress when samples are deformed in simple shear geometry. Two different classes of theoretical models have been developed to explain this nonlinear elastic response, which is neither predicted by rubber elasticity theory nor observed in elastomers or gels formed by flexible polymers. One model considers the response of isotropic networks of semiflexible polymers that have nonlinear force-elongation relations arising from their thermal fluctuations. The other considers networks of rigid filaments with linear force-elongation relations in which nonlinearity arises from nonaffine deformation and a shift from filament bending to stretching at increasing strains. Fibrin gels are a good experimental system to test these theories because the fibrin monomer assembles under different conditions to form either thermally fluctuating protofibrils with persistence length on the order of the network mesh size, or thicker rigid fibers. Comparison of rheologic and optical measurements shows that strain stiffening and negative normal stress appear at smaller strains than those at which filament orientation is evident from birefringence. Comparisons of shear to normal stresses and the strain-dependence of shear moduli and birefringence suggest methods to evaluate the applicability of different theories of rod-like polymer networks. The strain-dependence of the ratio of normal stress to shear stress is one parameter that distinguishes semiflexible and rigid filament models, and comparisons with experiments reveal conditions under which specific theories may be applicable.

Differential clinical significance of pre-, interim-, and post-treatment plasma Epstein-Barr virus DNA load in NK/T-cell lymphoma treated with P-GEMOX protocol.

Circulating EBV-DNA is an accurate biomarker of tumor load in extranodal natural killer (NK)/T cell lymphoma (ENKTL); however, its role in patients treated with P-GEMOX has not been evaluated. In this study, we examined plasma EBV-DNA of 99 patients at different time points by real-time quantitative polymerase chain reaction. Multivariate analysis revealed that ECOG PS score, response rate, and post-treatment EBV-DNA level were independent predictors of progression-free survival (PFS) and overall survival (OS). Positive post-treatment plasma EBV-DNA was associated with poor OS in ENKTL patients. The 3-year OS for patients with positive pre-, interim-, post-treatment EBV-DNA was significantly lower than that for patients with negative EBV-DNA; the values were 70.2% vs. 93.9% (p = .022), 53.8% vs. 99.1% (p < .001), and 40.6% vs. 91.8% (p < .001), respectively. We conclude that monitoring dynamic changes in plasma EBV-DNA in ENKTL patients treated with P-GEMOX could predict important outcomes such as OS.

Efficacy of combined gemcitabine, oxaliplatin and pegaspargase (P-gemox regimen) in patients with newly diagnosed advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with advanced-stage or relapsed/refractory ENKTL. We retrospectively investigated the efficacy and toxicity of combined gemcitabine, oxaliplatin, and pegaspargase (P-gemox) in these patients. A total of 35 patients with newly diagnosed stage III-IV, relapsed or refractory ENKTL were treated with 2 to 8 cycles of P-gemox: gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) injected intravenously and pegaspargase (2500 IU/m2) injected intramuscularly on day 1 and repeated every 2 weeks. Upon completion of treatment, the overall response rate was 80.0%, with a complete response in 51.4% of patients. The 1-, 2- and 3- year progression-free survival rates were 45.0%, 38.6% and 38.6%, and overall survival rates were 76.8%, 64.7% and 64.7%, respectively. Patients who attained a complete response showed better progression-free survival than those without a complete response (p = 0.01). The major adverse effects were hematologic toxicity and liver dysfunction. Grade 3/4 leucopenia and neutropenia occurred in 40.0% of patients. No treatment-related deaths occurred. These results indicate the P-gemox regimen is a safe and effective treatment for patients with newly diagnosed advanced-stage or relapsed/refractory ENKTL. We anticipate future prospective trials will confirm the efficacy.

Analysis of the efficacy and safety of a combined gemcitabine, oxaliplatin and pegaspargase regimen for NK/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Novel L-asparaginase-based treatment regimens, such as GELOX (gemcitabine, oxaliplatin, and L-asparaginase) and P-gemox (gemcitabine, oxaliplatin, and pegaspargase), have shown promising results against stage IE/IIE ENKTL. To define the general applicability of P-gemox, in a retrospective analysis we examined the efficacy and safety of P-gemox in a cohort of 117 patients with newly diagnosed or relapsed/refractory ENKTL. Treatment included 2 to 8 cycles of P-gemox: intravenous gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) and intramuscular pegaspargase (2500 IU/ m2) on day 1 and repeated every 2 weeks, or intravenous gemcitabine (1000 mg/m2) on days 1 and 8 and intravenous oxaliplatin (130 mg/m2) and intramuscular pegaspargase (2500 IU/m2) on day 1 and repeated every 3 weeks. Upon completion of treatment, the overall response rate was 88.8%, and responses were similar for newly diagnosed and relapsed/refractory patients. After a median follow-up of 17 months, the 3-year overall and progression-free survival rates were 72.7% and 57.8%, respectively. Multivariate analysis showed that CR after treatment was the most significant factor affecting survival. P-gemox thus appears to be an effective and well-tolerated treatment for patients with ENKTL.