Development of Nuclear Quadrupole Resonance Spectroscopic and Imaging Methods.

Solution-state nuclear magnetic resonance (NMR) of \sp1H and \sp{13}C nuclei in molecular species is very common as is solid-state NMR of \sp{13}C in a wide variety of substances. Yet many nuclei remain little studied by conventional NMR techniques, for example \sp2H, \sp{11}B, \sp{14}N, \sp{79}Br, \sp{81}Br, and \sp{93}Nb. One method for their study is nuclear quadrupole resonance (NQR). Briefly, the reason that quadrupolar nuclei are difficult to study with conventional NMR techniques is the exceedingly large line widths these nuclei exhibit in high magnetic fields. The first part of my dissertation deals with NQR spectroscopic techniques developed to obtain structural information on solids using three different line narrowing techniques: (1) The results of field swept \sp{93}Nb NMR experiments of \rm BaNb\sb{X}S\sb3 (x = 0.8,1) are presented with the Oxford 16/18 Tesla superconducting magnet at 4.2 K. (2) The development of a broadband NQR spectrometer having very wide spectral range from 200 to 300 MHz with automatic frequency selection and a novel automatically-tuned probe and the results of \sp{79}Br and \sp{81}Br NQR of some brominated aromatic compounds are discussed. (3) The development of a field cycling NQR spectrometer based on a conventional NMR, a high speed linear stepping motor, and an Oxford gas flow cryostat is described with some \sp2H and \sp{14}N NQR spectra. The second part of my dissertation describes novel \sp{11}B and \sp{14}N NQR imaging techniques that use field cycling as a line narrowing technique and therefore, is a combination of both NQR spectroscopy and NMR imaging. A demonstration of two-dimensional \sp1H imaging using an unmodified solution-state NMR spectrometer is also presented

Third-order exceptional point in an ion-cavity system

We investigate a scheme for observing the third-order exceptional point (EP3) in an ion-cavity setting. In the lambda-type level configuration, the ion is driven by a pump field, and the resonator is probed with another weak laser field. We exploit the highly asymmetric branching ratio of an ion's excited state to satisfy the weak-excitation limit, which allows us to construct the non-Hermitian Hamiltonian $(H_{\textrm{nH}})$. Via fitting the cavity-transmission spectrum, the eigenvalues of $H_{\textrm{nH}}$ are obtained. The EP3 appears at a point where the Rabi frequency of the pump laser and the atom-cavity coupling constant balance the loss rates of the system. Feasible experimental parameters are provided.Comment: 9 pages, 6 figure

Ion trap with gold-plated alumina: substrate and surface characterization

We describe a complete development process of a segmented-blade linear ion trap. Alumina substrate is characterized with an X-ray diffraction and loss-tangent measurement. The blade is laser-micromachined and polished, followed by the sputtering and gold electroplating. Surface roughness is examined at each step of the fabrication via both electron and optical microscopies. On the gold-plated facet, we obtain a height deviation of tens of nanometers in the vicinity of the ion position. Trapping of laser-cooled $^{174}$Yb$^{+}$ ions is demonstrated.Comment: 7 pages, 6 figure

International comparison of the factors influencing reimbursement of targeted anti-cancer drugs

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. Methods: We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Results: Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = −0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Conclusions: Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.Peer Reviewe

Exercise does not increase cyclooxygenase-2 myocardial levels in young or senescent hearts

Increased myocardial cyclooxygenase-2 (COX-2) activity is essential for late phase ischemic preconditioning (IPC). Currently unknown is whether cardioprotection elicited by exercise also involves elevated myocardial COX-2 activity. This investigation tested whether aerobic exercise elevates myocardial COX-2 protein content or enzyme activity in young and senescent male Fisher 344 rats assigned to sedentary or cardioprotective endurance exercise treatments (3 consecutive days of treadmill exercise, 60 min/day @~70% VO2max). Assay of cardiac COX-2 protein content, catalytic activity, and inducible nitric oxide synthase (iNOS) protein content reveal that exercise did not alter COX-2 activity (PGE2, p = 0.866; PGF1α, p = 0.796) or protein levels (p = 0.397) within young or senescent hearts. In contrast, myocardial iNOS, an up-stream mediator of COX-2 expression, was over-expressed by an average of 37% in aged hearts (p = 0.005), though iNOS was not influenced by exercise. Findings reveal exercise does not elevate cardiac COX-2 activity and suggests that mechanisms responsible for cardioprotection differ between IPC and aerobic exercise

Polymorphisms in Genes That Regulate Cyclosporine Metabolism Affect Cyclosporine Blood Levels and Clinical Outcomes in Patients Who Receive Allogeneic Hematopoietic Stem Cell Transplantation

In patients who received allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the correlations between single nucleotide polymorphisms (SNPs) in genes that regulate cyclosporine metabolism and clinical outcomes. All patients received sibling-matched HSCT. DNA samples of patients and donors were analyzed for 4 SNPs: MDR1 +1236C>T (rs1128503), +2677G>T>A (rs2032582), +3435C>T (rs1045642), and CYP3A5 +6986G>A (rs776746). A total of 156 patients (median age 40 years) were analyzed. Nineteen patients received HSCT for nonmalignant disease. The CYP3A5 +6986AA genotype was associated with a high cyclosporine blood level after transplantation. However, this genotype was not related to any particular clinical outcome. In contrast, the MDR1 +1236C>T SNP was correlated with specific clinical outcomes. When neither the donor nor the recipient had the CC genotype of MDR1 +1236, patients had lower creatinine levels (P < .001) and less transplantation-related mortality (TRM) (P = .012). These patients also showed longer overall survival (OS) in both univariate (P = .003) and multivariate (P = .003) analyses. Although the CYP3A5 +6986AA genotype was correlated with a high blood cyclosporine concentration, lack of the MDR1 +1236CC genotype in both the donor and recipient was correlated with less TRM and a longer OS in patients who received allogeneic HSCT

The molecular pathogenesis of Trichilemmal carcinoma

Background Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis. Methods Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes. Results DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213*, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients (TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362*), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse. Conclusions We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Grant number NRF2018R1A4A1022513). FFPE Sample handling and next generation sequencing was performed using the below funding sourc

Modifications of the Fine Structure of the Incisor Pulp of the Guinea Pig during Fxperimental Scurvy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68076/2/10.1177_00220345660450030301.pd

Transcriptional signatures of the BCL2 family for individualized acute myeloid leukaemia treatment

Abstract Background Although anti-apoptotic proteins of the B-cell lymphoma-2 (BCL2) family have been utilized as therapeutic targets in acute myeloid leukaemia (AML), their complicated regulatory networks make individualized therapy difficult. This study aimed to discover the transcriptional signatures of BCL2 family genes that reflect regulatory dynamics, which can guide individualized therapeutic strategies. Methods From three AML RNA-seq cohorts (BeatAML, LeuceGene, and TCGA; n = 451, 437, and 179, respectively), we constructed the BCL2 family signatures (BFSigs) by applying an innovative gene-set selection method reflecting biological knowledge followed by non-negative matrix factorization (NMF). To demonstrate the significance of the BFSigs, we conducted modelling to predict response to BCL2 family inhibitors, clustering, and functional enrichment analysis. Cross-platform validity of BFSigs was also confirmed using NanoString technology in a separate cohort of 47 patients. Results We established BFSigs labeled as the BCL2, MCL1/BCL2, and BFL1/MCL1 signatures that identify key anti-apoptotic proteins. Unsupervised clustering based on BFSig information consistently classified AML patients into three robust subtypes across different AML cohorts, implying the existence of biological entities revealed by the BFSig approach. Interestingly, each subtype has distinct enrichment patterns of major cancer pathways, including MAPK and mTORC1, which propose subtype-specific combination treatment with apoptosis modulating drugs. The BFSig-based classifier also predicted response to venetoclax with remarkable performance (area under the ROC curve, AUROC = 0.874), which was well-validated in an independent cohort (AUROC = 0.950). Lastly, we successfully confirmed the validity of BFSigs using NanoString technology. Conclusions This study proposes BFSigs as a biomarker for the effective selection of apoptosis targeting treatments and cancer pathways to co-target in AML