Application of the Shifting Method as a Technique to Correct for the Background in Quantitative Analysis by Open-Path FTIR

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91921/1/awmapub.pd

Gas phase RDX decomposition pathways using coupled cluster theory

Electronic and free energy barriers for a series of gas-phase RDX decomposition mechanisms have been obtain using coupled cluster singles, doubles, and perturbative triples with complete basis set (CCSD(T)/CBS) electronic energies for MBPT(2)/cc-pVTZ structures. Importantly, we have located a well-defined transition state for NN homolysis, in the initial RDX decomposition step, thereby obtaining a true barrier for this reaction. These calculations support the view that HONO elimination is preferred at STP over other proposed mechanisms, including NN homolysis, “triple whammy” and NONO isomerization. Indeed, our calculated values of Arrhenius parameters are in agreement with experimental findings for gas phase RDX decomposition. We also investigate a number of new pathways leading to breakdown of the intermediate formed by the initial HONO elimination, and find that NN homolysis in this intermediate has an activation energy barrier comparable with that computed for HONO elimination

Deciphering the Potential Coding of Human Cytomegalovirus: New Predicted Transmembrane Proteome

CMV is a major cause of morbidity and mortality in immunocompromised individuals that will benefit from the availability of a vaccine. Despite the efforts made during the last decade, no CMV vaccine is available. An ideal CMV vaccine should elicit a broad immune response against multiple viral antigens including proteins involved in virus-cell interaction and entry. However, the therapeutic use of neutralizing antibodies targeting glycoproteins involved in viral entry achieved only partial protection against infection. In this scenario, a better understanding of the CMV prote-ome potentially involved in viral entry may provide novel candidates to include in new potential vaccine design. In this study, we aimed to explore the CMV genome to identify proteins with puta-tive transmembrane domains to identify new potential viral envelope proteins. We have performed in silico analysis using the genome sequences of nine different CMV strains to predict the trans-membrane domains of the encoded proteins. We have identified 77 proteins with transmembrane domains, 39 of which were present in all the strains and were highly conserved. Among the core proteins, 17 of them such as UL10, UL139 or US33A have no ascribed function and may be good candidates for further mechanistic studies

Monotherapy with boosted protease inhibitors as antiretroviral treatment simplification strategy in the clinical setting

Antiretroviral treatment simplification with darunavir/ritonavir or lopinavir/ritonavir monotherapy maintains sustained HIV viremia suppression in clinical trials. However, data about the efficacy of this strategy in routine clinical practice is still limited, and no direct comparison between darunavir/ritonavir and lopinavir/ritonavir has been performed to date. We retrospectively studied all HIV-1-infected subjects who initiated monotherapy with darunavir/ritonavir or lopinavir/ritonavir while having plasma VL<50 c/mL, and had at least 1 subsequent follow-up visit in our clinic. When two consecutive PI-monotherapy regimens were used, each regimen was considered separately. The primary endpoint was the percentage of patients who maintained virological suppression (HIV-1 VL <50 c/mL) through follow-up. Virological failure was defined as at least two consecutive HIV-1 VL >50 c/mL. We also evaluated other reasons for treatment discontinuation. Analyses were performed considering all regimens (full dataset analysis) either as “on treatment” or as “treatment switch equals failure”. Five hundred and seventy-three PI-monotherapy regimens corresponding to 520 subjects were included, 262 with darunavir/ritonavir and 311 with lopinavir/ritonavir. Medians (IQR) follow-up were 50 (26.3–107.6) and 85.6 (36.9–179.1) weeks for subjects on darunavir/ritonavir and lopinavir/ritonavir, respectively (p<0.001). Overall, 67 (11.7%) subjects experienced virological failure, 23 (8.7%) were on darunavir/ritonavir and 42 (13.5%) were on lopinavir/ritonavir (p=0.796). Two hundred and three (77.5%) patients on darunavir/ritonavir and 154 (49.5%) on lopinavir/ritonavir maintained virological suppression in the “treatment switch equals failure” (p=0.002). Other reasons for treatment discontinuation were gastrointestinal toxicity and dyslipidemia in 7.2% and 5.9% of cases, respectively. Gastrointestinal toxicities and dyslipidemia leading to treatment discontinuation were more frequent in patients on lopinavir/ritonavir (10.6% and 10.3%, respectively) than in patients on darunavir/ritonavir (3.1% and 0.8%, respectively). Monotherapy with darunavir/ritonavir or lopinavir/ritonavir as simplification strategy appears to be effective and safe in subjects with virological suppression in clinical practice. Virological efficacy seems to be similar between regimens. However, rates of discontinuation due to toxicities were higher in subjects on lopinavir/ritonavir than darunavir/ritonavir

Radiation therapy and photodynamic therapy for biliary tract and ampullary carcinomas

The purpose of radiation therapy for unresectable biliary tract cancer is to prolong survival or prolong stent patency, and to provide palliation of pain. For unresectable bile duct cancer, there are a number of studies showing that radiation therapy is superior to the best supportive care. Although radiation therapy is used in many institutions, no large randomized controlled trials (RCTs) have been performed to date and the evidence level supporting the superiority of this treatment is low. Because long-term relief of jaundice is difficult without using biliary stenting, a combination of radiation therapy and stent placement is commonly used. As radiation therapy, external-beam radiation therapy is usually performed, but combined use of intraluminal brachytherapy with external beam radiation therapy is more useful for making the treatment more effective. There are many reports demonstrating improved response rates as well as extended survival and time to recurrence achieved by this combination therapy. Despite the low level of the evidence, this combination therapy is performed at many institutions. It is expected that multiinstitutional RCTs will be carried out. Unresectable gallbladder cancer with a large focus is usually extensive, and normal organs with high radio sensitivity exist contiguously with it. Therefore, only limited anticancer effects are to be expected from external beam radiation therapy for this type of cancer. The number of reports on ampullary cancer is small and the role of radiation therapy in this cancer has not been established. Combination treatment for ampullary cancer consists of either a single use of intraoperative radiation therapy, postoperative external beam radiation therapy or intraluminal brachytherapy, or a combination of two or three of these therapies. Intraoperative radiation therapy is superior in that it enables precise irradiation to the target site, thereby protecting adjacent highly radiosensitive normal tissues from irradiation. There are reports showing extended survival, although not significant, in groups undergoing intraoperative or postoperative radiation therapy compared with groups without radiation therapy. To date, there are no reports of large RCTs focusing on the significance of radiation therapy as a postoperative adjuvant treatment, so its usefulness as a postoperative adjuvant treatment is not proven. An alternative treatment is photodynamic therapy. There is an RCT demonstrating that, in unresectable bile duct cancer, extended survival and improved quality of life (QOL) have been achieved through a combination of photodynamic therapy and biliary stenting, compared with biliary stenting alone. Results from large RCTs are desired

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX