University at Buffalo

About: University at Buffalo is a education organization based out in Buffalo, New York, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 33773 authors who have published 63840 publications receiving 2278954 citations. The organization is also known as: UB & State University of New York at Buffalo.

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Abstract: Importance Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13,MLH1[including one with constitutionalMLH1methylation]; 16,MSH2; 1,MSH2/monoallelicMUTYH; 2,MSH6; 5,PMS2); 1 patient had theAPCc.3920T>A, p.I1307K mutation and aPMS2variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelicMUTYHmutations); and 1 patient had somaticMLH1methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5,APC; 1,APC/PMS2; 2, biallelicMUTYH; 1,SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3,ATM; 1,ATM/CHEK2; 2,BRCA1; 4,BRCA2; 1,CDKN2A; 2,PALB2); 10 patients had mutations in low-penetrance CRC genes (3,APCc.3920T>A, p.I1307K; 7, monoallelicMUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease

Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1 )a ndLRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q10, rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSCderived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.

Transverse-Momentum and Pseudorapidity Distributions of Charged Hadrons in pp Collisions at root s=7 TeV

Abstract: Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at root s = 7 TeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity dN(ch)/d eta vertical bar(vertical bar eta vertical bar<0.5) = 5.78 +/- 0.01(stat) +/- 0.23(stat) for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from root s = 0.9 to 7 TeV is [66.1 +/- 1.0(stat) +/- 4.2(syst)]%. The mean transverse momentum is measured to be 0.545 +/- 0.005(stat) +/- 0.015(syst) GeV/c. The results are compared with similar measurements at lower energies.

Formation and Stability of N-Heterocyclic Carbenes in Water: The Carbon Acid pKa of Imidazolium Cations in Aqueous Solution

Abstract: We report second-order rate constants kDO (M-1 s-1) for exchange for deuterium of the C(2)-proton of a series of simple imidazolium cations to give the corresponding singlet imidazol-2-yl carbenes in D2O at 25 degrees C and I = 1.0 (KCl). Evidence is presented that the reverse protonation of imidazol-2-yl carbenes by solvent water is limited by solvent reorganization and occurs with a rate constant of kHOH = kreorg = 10(11) s-1. The data were used to calculate reliable carbon acid pK(a)s for ionization of imidazolium cations at C(2) to give the corresponding singlet imidazol-2-yl carbenes in water: pKa = 23.8 for the imidazolium cation, pKa = 23.0 for the 1,3-dimethylimidazolium cation, pKa = 21.6 for the 1,3-dimethylbenzimidazolium cation, and pKa = 21.2 for the 1,3-bis-((S)-1-phenylethyl)benzimidazolium cation. The data also provide the thermodynamic driving force for a 1,2-hydrogen shift at a singlet carbene: K12 = 5 x 10(16) for rearrangement of the parent imidazol-2-yl carbene to give neutral imidazole in water at 298 K, which corresponds to a favorable Gibbs free energy change of 23 kcal/mol. We present a simple rationale for the observed substituent effects on the thermodynamic stability of N-heterocyclic carbenes relative to a variety of neutral and cationic derivatives that emphasizes the importance of the choice of reference reaction when assessing the stability of N-heterocyclic carbenes.

Toward Efficient Multi-Keyword Fuzzy Search Over Encrypted Outsourced Data With Accuracy Improvement

Abstract: Keyword-based search over encrypted outsourced data has become an important tool in the current cloud computing scenario. The majority of the existing techniques are focusing on multi-keyword exact match or single keyword fuzzy search. However, those existing techniques find less practical significance in real-world applications compared with the multi-keyword fuzzy search technique over encrypted data. The first attempt to construct such a multi-keyword fuzzy search scheme was reported by Wang et al. , who used locality-sensitive hashing functions and Bloom filtering to meet the goal of multi-keyword fuzzy search. Nevertheless, Wang’s scheme was only effective for a one letter mistake in keyword but was not effective for other common spelling mistakes. Moreover, Wang’s scheme was vulnerable to server out-of-order problems during the ranking process and did not consider the keyword weight. In this paper, based on Wang et al. ’s scheme, we propose an efficient multi-keyword fuzzy ranked search scheme based on Wang et al. ’s scheme that is able to address the aforementioned problems. First, we develop a new method of keyword transformation based on the uni-gram, which will simultaneously improve the accuracy and creates the ability to handle other spelling mistakes. In addition, keywords with the same root can be queried using the stemming algorithm. Furthermore, we consider the keyword weight when selecting an adequate matching file set. Experiments using real-world data show that our scheme is practically efficient and achieve high accuracy.