A study on rheological properties of blood and improvements with high-voltage plasma discharge

Blood behaves as a shear-thinning non-Newtonian fluid where its viscosity varies due to both the deformability and aggregation of RBCs with the interaction with macro-molecules in blood plasma. The elevated whole blood viscosity (WBV), which indicates the increased frictional resistance between a moving blood and stationary vessel walls, has been suggested as one of the major determinants or risk factors of atherosclerosis diseases (i.e., cardiovascular diseases, stroke, and peripheral arterial diseases etc.) and microvascular disorders (i.e., diabetic retinopathy, nephrophathy, and neuropathy etc.) by causing both the endothelial injury of vessel walls and poor perfusion at capillaries.In order to investigate the shear-thinning non-Newtonian behavior of blood in regards to the effects of increased wall shear stress and impaired oxygen delivery on various diseases that might be caused by hyperviscosity, the present study was focused on the studies of rheological properties of blood by examining the WBV profiles over a pathologically wide range of shear rates using a scanning capillary tube viscometer (SCTV) and their improvements using high-voltage plasma discharge.Firstly, a new hematocrit-correction model using the Casson model was proposed to correct the measured WBVs of different blood samples with different hematocrits to a standard hematocrit of 45 %, a process which is needed to compare the effect of intrinsic rheological properties or other determinants on blood viscosity for different blood samples. Without the measurement of plasma viscosity, the new model showed about 4 to 6 times more accurate and less deviations than the conventional Matrai's model.Secondly, a new method of measuring the electric conductivity of whole blood was introduced for the purpose of hematocrit determination, demonstrating a simple but accurate hematocrit measurement by employing a low-frequency squarewave voltage signal in a conductance cell, without the usual error associated with the sedimentation of erythrocytes.Thirdly, a new physical treatment method with the application of highvoltage plasma discharges (i.e. DBD and corona discharge) followed by filtration of the coagulated particles was proposed. The results indicated that WBV could be reduced by 9.1 % and 17.7 % for systolic blood viscosity (SBV) and diastolic blood viscosity (DBV), respectively, from the baseline values when DBD-treated blood plasma was filtered prior to mixing with red blood cells. When treated with the corona discharge for 60 pulses, DBV and LDL concentration dropped by 30.1 % and 31.5 %, respectively, from the baseline values.Lastly, a new opaque standard viscosity fluid (SVF) was proposed using maltose with 55 % of concentration to replicate a shear-thinning non-Newtonian behavior of blood for different shear rates. The produced viscosity profiles from three different levels of SVFs provided low-, medium-, and high-standard viscosity fluids that can be used for the performance test of any blood viscometers over a wide range of shear rates. The applicability of new opaque SVFs was demonstrated by dye concentration test, repeatability test, and degradation test.Ph.D., Mechanical Engineering -- Drexel University, 201

DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy

Raw Garlic Consumption and Risk of Liver Cancer: A Population-Based Case-Control Study in Eastern China.

Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62-0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01-0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00-0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population

Allelic based gene-gene interactions in rheumatoid arthritis

The detection of gene-gene interaction is an important approach to understand the etiology of rheumatoid arthritis (RA). The goal of this study is to identify gene-gene interaction of SNPs at the allelic level contributing to RA using real data sets (Problem 1) of North American Rheumatoid Arthritis Consortium (NARAC) provided by Genetic Analysis Workshop 16 (GAW16). We applied our novel method that can detect the interaction by a definition of nonrandom association of alleles that occurs when the contribution to RA of a particular allele inherited in one gene depends on a particular allele inherited at other unlinked genes. Starting with 639 single-nucleotide polymorphisms (SNPs) from 26 candidate genes, we identified ten two-way interacting genes and one case of three-way interacting genes. SNP rs2476601 on PTPN22 interacts with rs2306772 on SLC22A4, which interacts with rs881372 on TRAF1 and rs2900180 on C5, respectively. SNP rs2900180 on C5 interacts with rs2242720 on RUNX1, which interacts with rs881375 on TRAF1. Furthermore, rs2476601 on PTPN22 also interacts with three SNPs (rs2905325, rs1476482, and rs2106549) in linkage disequilibrium (LD) on IL6. The other three SNPs (rs2961280, rs2961283, and rs2905308) in LD on IL6 interact with two SNPs (rs477515 and rs2516049) on HLA-DRB1. SNPs rs660895 and rs532098 on HLA-DRB1 interact with rs2834779 and four SNPs in LD on RUNX1. Three-way interacting genes of rs10229203 on IL6, rs4816502 on RUNX1, and rs10818500 on C5 were also detected

Who Are Less Likely to Receive Subsequent Chemotherapy Beyond First-Line Therapy for Advanced Non-small Cell Lung Cancer?: Implications for Selection of Patients for Maintenance Therapy

BackgroundProspective studies have implied that maintenance therapy for non-small cell lung cancer (NSCLC) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy. The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy, by evaluating which patients would be less likely to receive second-line therapy.MethodsClinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were reviewed retrospectively. Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy. Clinical characteristics between the two groups were compared.ResultsA total of 271 patients were eligible for analysis, and 39 patients (14.4%) received only first-line therapy. Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy, large volume of initial target lesions (sum of long diameters ≥70 mm), or smaller decrease in target lesions (decrease <20%) after first-line therapy. Median overall survival of the 143 patients (52.8%) with at least one of these characteristics (16.3 months) was significantly shorter than that of patients without any of these characteristics (23.5 months, p = 0.007).ConclusionMaintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first-line therapy, large initial target lesions, or smaller decrease in target lesions after first-line therapy

Evaluation of Degradation in Nanofilled Adhesive Resins Using Quantitative Light-Induced Fluorescence

The aim of this study was to evaluate degradation in commercial dental nanofilled adhesive resins using quantitative light-induced fluorescence (QLF). Three adhesives were selected: D/E resin (DR), Single Bond Plus (SB), and G-Bond (GB). The adhesives were mixed with porphyrin for the QLF analysis. Specimens were prepared by dispensing blended adhesives into a flexible mold and polymerizing. Then, the QLF analysis of the specimens was done and the porphyrin values (Simple Plaque Score and ΔR) were measured. After thermocycling of the specimens (5000 cycles, 5 to 55°C) for the degradation, the specimens were assayed by QLF again. The porphyrin values were analyzed using paired t-test at a 95% confidence level. A significant reduction in SPS was observed in all groups after thermocycling. The ΔR significantly decreased after thermocycling except area ΔR30 of SB group. Overall, porphyrin values decreased after thermocycling which indicates that the degradation of the adhesive resins may be measured by the change of porphyrin value. The QLF method could be used to evaluate the degradation of adhesive resin

The Actual Five-year Survival Rate of Hepatocellular Carcinoma Patients after Curative Resection

The five-year survival rate of patients after curative resection of hepatocellular carcinoma (HCC) has been reported to be 30 to 50%, however the actual survival rate may be different. We analyzed the actual 5-year survival rate and prognostic factors after curative resection of HCC. Retrospective analysis was performed on 63 HCC patients who underwent curative resection from 1998 to 1999. A total of 63 cases were reviewed, consisting of 53 men and 10 women, with a median age of 49 years. These cases included all four pathologic T stages (pT stage) and had the following representation: stage 1 (1 case), stage 2 (17 cases), stage 3 (38 cases), and stage 4 (7 cases). In our study, the actual 5-year survival rate was 57.0% and the median survival time was 60 months. In addition, the patients in our study had an actual 5-year disease-free survival rate of 50.2% and a median disease-free survival time of 46 months. Thirty-one patients had recurrences, with a majority occurring within one year (65%). These patients with early recurrences had a poor actual 5-year survival rate of 5%. A univariate analysis showed that the prognostic factors influencing survival rate were the presence of satellite nodules, increased pT stage, HCC recurrence, and the time to recurrence (within one year). Interestingly, microvascular invasion made a difference in survival rate but was not statistically significant (p = 0.08). Furthermore, factors influencing the disease free survival rate include the presence of satellite nodules, microvascular invasion, and pT stage. Multivariate analysis identified pT stage as the only statistically related factor in determining the disease-free survival rate. The most important prognostic factor of HCC is recurrence. Moreover, the major risk factor for recurrence is an advanced pT stage. Therefore, performing prospective studies of postoperative adjuvant therapy is necessary to prevent recurrences after hepatic resection. Furthermore, active preventative treatment and early diagnosis of recurrences should be of the highest priority in the care of high-risk patient groups that have an advanced pT stage

Comprehensive Analysis of Transcription Factor-Based Molecular Subtypes and Their Correlation to Clinical Outcomes in Small-Cell Lung Cancer

BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. FINDINGS: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). INTERPRETATION: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response