Bioinformatics Analysis of Humoral Immune Response and Protein Microarray for Biomarker Discovery.

Early detection is the best defense which could significantly improve the cancer survival rate in several cancers including melanoma and pancreatic cancer. A promising approach to discover biomarkers for early detection involves using the humoral immune response against tumor proteins. Together with advances in proteomics, in particular a high throughput protein microarray platform, humoral immune response studies have enabled a breakthrough in developing global screening of the highly complex plasma proteome for biomarkers for early detection. In this dissertation, we attempt to integrate proteomics and bioinformatics approaches to analyze signals from protein microarray data for the reliable identification of differentially expressed proteins under different biological conditions. First, we present a study comparing outlier-based to traditional mean-based approaches in differential expression analysis with applications in protein microarray data in heterogeneous diseases. Our investigation uses a glycoproteomics dataset from a melanoma study, an original simulation-based approach to benchmarking, and a new data visualization technique to assess the potential for methods that explicitly target heterogeneous patterns of differential expression to give improved performance relative to traditional approaches based on group-wise comparison of means. Results include identifications of 1 significant feature using outlier statistics and 15 significant features using t-statistics from a melanoma dataset of 43 samples and 47 features. Next, we apply the outlier strategy to a protein microarray dataset from a pancreatic cancer study with sera from 37 pancreatic cancers, 24 chronic pancreatitis and 23 normal to identify protein biomarkers that are differentially expressed in only a subset of cancer samples. Three protein markers exhibiting outlier patterns exclusive to cancer sera and no outliers in normal sera are identified by mass spectrometry and confirmed by a follow-up study with an independent dataset. The next study presents the application of a label-free quantitation approach for measuring changes in protein abundance level associated with phosphorylation, a major mechanism of tumorigenesis. Results include identifications of differentially expressed post-translational modified proteins such as phosphorylated lamin-A/C, isoforms-A and GTPase-activating protein binding protein-1 in pancreatic cancer. Together, this dissertation contributes two approaches to biomarker discovery using protein microarrays and the humoral immune response and LC-MS/MS and label-free quantitation.Ph.D.BioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89673/1/huyvuong_1.pd

Universality of Spectral Independence with Applications to Fast Mixing in Spin Glasses

We study Glauber dynamics for sampling from discrete distributions $\mu$ on the hypercube $\{\pm 1\}^n$. Recently, techniques based on spectral independence have successfully yielded optimal $O(n)$ relaxation times for a host of different distributions $\mu$. We show that spectral independence is universal: a relaxation time of $O(n)$ implies spectral independence. We then study a notion of tractability for $\mu$, defined in terms of smoothness of the multilinear extension of its Hamiltonian -- $\log \mu$ -- over $[-1,+1]^n$. We show that Glauber dynamics has relaxation time $O(n)$ for such $\mu$, and using the universality of spectral independence, we conclude that these distributions are also fractionally log-concave and consequently satisfy modified log-Sobolev inequalities. We sharpen our estimates and obtain approximate tensorization of entropy and the optimal $\widetilde{O}(n)$ mixing time for random Hamiltonians, i.e. the classically studied mixed $p$-spin model at sufficiently high temperature. These results have significant downstream consequences for concentration of measure, statistical testing, and learning

Dimension reduction for maximum matchings and the Fastest Mixing Markov Chain

Let $G = (V,E)$ be an undirected graph with maximum degree $\Delta$ and vertex conductance $\Psi^*(G)$. We show that there exists a symmetric, stochastic matrix $P$, with off-diagonal entries supported on $E$, whose spectral gap $\gamma^*(P)$ satisfies $$\Psi^*(G)^{2}/\log\Delta \lesssim \gamma^*(P) \lesssim \Psi^*(G).$$ Our bound is optimal under the Small Set Expansion Hypothesis, and answers a question of Olesker-Taylor and Zanetti, who obtained such a result with $\log\Delta$ replaced by $\log|V|$. In order to obtain our result, we show how to embed a negative-type semi-metric $d$ defined on $V$ into a negative-type semi-metric $d'$ supported in $\mathbb{R}^{O(\log\Delta)}$, such that the (fractional) matching number of the weighted graph $(V,E,d)$ is approximately equal to that of $(V,E,d')$.Comment: 6 page

Footprint of increased anthropogenic disturbance elevates termite pest status

Tese de doutoramento em Ciências Farmacêuticas, na especialidade de Farmacognosia e Fitoquímica, apresentada à Faculdade de Farmácia da Universidade de CoimbraCymbopogon citratus (DC). Stapf (Poaceae), commonly known as lemongrass, is a tropical perennial shrub originated from the Southeast Asia. This plant is reported to possess antifungal, insecticidal, anti-diabetic, anti-septic, anti-mutagenic, anti-carcinogenic activities as well as anti-inflammatory. In fact, aqueous extracts of dried leaves are used all over the year in folk medicine for the treatment of peptic ulcers and inflammatory conditions. Recently, some phenolic compounds, such as luteolin and apigenin glycosides and condensed tannins, were identified and related to both antioxidant and anti-inflammatory properties. The purposes of this work were to i) validate an analytical method for quantification of phenolic compounds of C. citratus; ii) study the influence of harvest time and plant quality on the phenolic composition and antioxidant activity; iii) characterize the tannins; iv) validate the traditional uses of lemongrass infusion as anti-inflammatory in vivo; v) obtain a topical formulation to evaluate the phenolic compounds permeation and their anti-inflammatory activity; vi) trace the pharmacokinetic profile of the main phenolic compounds in rats. Three different extracts: infusion (CcI), 50% aqueous ethanol (CcM50%) and ethanol (CcM100%) extracts were prepared and a simple and efficient RP-HPLC-PDA method was successfully validated for simultaneous identification and quantification of phenolic acids and flavonoids. Infusions were also obtained from different harvest dates (April, June, July, August and September) and quality grades (High, Medium and Low). It was verified that the content on polyphenols and the antioxidant capacity of CcI is strongly related with the quality of the plant. The total phenols assay showed a substantial loss from August to September. It was possible to find out the best month to harvest the plant to get the most of each phenolic group: April and June for hydroxycinnamic acids; June and September for flavonoids; June, July and August for tannins. Regardless the group of phenolic compound addressed, its content was always inversely proportional to the degree of leaves ageing. For all tested oxidant species, the high-quality samples exhibited the best antioxidant results. CcI was fractionated by column chromatography and polyphenol-rich fractions, namely phenolic acids (CcPA), flavonoids (CcF) and tannins (CcT) were obtained. CcT was characterized by HPLC-PDA-ESI/MSn, revealing the presence of proanthocyanidin hetero-dimers, along with some common procyanidin dimers. These hetero-dimeric flavan structures have been described for the first time in lemongrass and consist of apigeniflavan or luteoliflavan units linked to a flavanone, either naringenin or eriodictyol, and may occur as aglycone or glycosylated forms. For the in vivo assays, CcI, CcF and CcT were tested. CcI administered before and after ethanol stimulus, significantly reduced the incidence and severity of gastric lesions and, consequently, the ulcer index, corroborating the traditional medicinal use of this plant to ameliorate gastritis and/or peptic ulcers symptoms. On the other hand, CcI, CcF and CcT were orally administered to rats, in order to evaluate the anti-inflammatory effect at the carrageenan-induced paw edema assay. The observed effect by CcI (68.24 mg/kg), 82.30% of edema inhibition, was very similar to that obtained by the reference NSAID used (diclofenac, 10 mg/kg), 84.00%. On the other hand, flavonoid (7.42 mg/kg) and the tannin-rich (5.96 mg/kg) fractions significantly contributed for the anti-inflammatory activity on the edema volume (59 and 61%, respectively). The topical anti-inflammatory activity of CcI was also addressed. The results suggest that flavonoids, mainly, luteolin 7-O-neohesperidoside, cassiaoccidentalin B, carlinoside and cynaroside, may contribute to the topical anti-inflammatory effect. CcF (0.6%), CcT (0.3%) and CcF+CcT (0.66%+0.34%) topical formulations were also tested, and the results obtained suggest that tannins and flavonoids also possess a significant activity and that a synergistic mechanism of action may occur. In fact, edema inhibitions of 43%, 47% and 59% were respectively verified, being CcF+CcT effect very close to that of 1% diclofenac (65.9%). Pharmacokinetic analysis was performed in plasma, liver and kidney and showed that the compounds present in CcI are not detected in vivo after a single-dose oral administration. In contrary, the metabolites, luteolin 7-O-glucuronide and luteolin 3’-O-sulfate, present at the highest bioavailability, are probably the main responsible for the anti-inflammatory activity previously reported. In conclusion, this work has developed a method to quantify the phenolic compounds contained in C. citratus; pointed the importance of harvesting and storing the plant material, in order to take the maximum advantages from the phenolic compounds use; and demonstrated, in safe doses, its anti-inflammatory activity, using an in vivo approach, which supports the traditional use of lemongrass infusion. Furthermore, C. citratus leaves flavonoids and tannins were highlighted as bioactive compounds, encouraging the development of new anti-inflammatory drugs or nutraceuticals

Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome:a retrospective cohort study

BACKGROUND: Conventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory implantation rates can be sustained. The objective of this study was to assess the live-birth rate and incidence of OHSS after GnRHa trigger and intensive luteal steroid support compared to traditional hCG trigger and conventional luteal support in OHSS high risk Asian patients. METHODS: We conducted a retrospective cohort study of 363 women exposed to GnRHa triggering with intensive luteal support compared with 257 women exposed to conventional hCG triggering. Women at risk of OHSS were defined by ovarian response ≥15 follicles ≥12 mm on the day of the trigger. RESULTS: Live-birth rates were similar in both groups GnRHa vs hCG; 29.8% vs 29.2% (p = 0.69). One late onset severe OHSS case was observed in the GnRHa trigger group (0.3%) compared to 18 cases (7%) after hCG trigger. CONCLUSIONS: GnRHa trigger combined with intensive luteal steroid support in this group of OHSS high risk Asian patients can facilitate fresh embryo transfer, however, in contrast to previous reports the occurrence of late onset OHSS was not completely eliminated

Long-term outcomes of primary cardiac malignant tumors: Difference between African American and Caucasian population

BACKGROUND: The survival outcome for primary cardiac malignant tumors (PMCTs) based on race has yet to be fully elucidated in previously published literature. This study aimed to address the general long-term outcome and survival rate differences in PMCTs among African Americans and Caucasian populations. METHODS: The 18 cancer registries database from the Surveillance, Epidemiology, and End Results (SEER) Program from 1975 to 2016 were utilized. Ninety-four African American (AA) and 647 Caucasian (CAU) patients from the SEER registry were available for survival analysis. The log-rank test was used to compare the difference in mortality between two populations and presented by the Kaplan-Meier curves. A multivariate Cox proportional hazards regression was used to determine the independent predictors of all-cause mortality. RESULTS: The overall 30-day, 1-year, and 5-year survival rates were 74%, 44.3%, and 16.6%, respectively, with a median survival of 10 months. There was no significant difference in survival rate between the two races (p-value = 0.55). The 1-year survival rate improved significantly during the study timeline in the AA population (13.3% during 1975-1998, 40.9% during 1999-2004, 50% during 2005-2010, and 59.7% during 2011-2016, p-value = 0.0064). Age of diagnosis, type of tumor, disease stage, and chemotherapy administration are the main factors that predict survival outcomes of PMCT patients. Interactive nomogram was developed based on significant predictors. CONCLUSIONS: PMCTs have remained one of the most lethal diseases with poor survival outcome. Survival rate improved during the timeline in AA patients, but in general, racial differences in survival outcome were not observed