RESUMEN
Objective: Previous studies have shown that first-line (1L) maintenance therapy (MT) with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab improves outcomes among patients with advanced ovarian cancer (OC); however, these treatments are underutilized. This study aimed to provide a real-world understanding of MTs among patients with advanced OC who received 1L platinum-based chemotherapy (PBC). Methods: A retrospective chart review using iKnowMed electronic health records to identify patients aged ≥18 years with advanced OC who initiated 1L PBC between January 1, 2018-December 31, 2020. Following 1L PBC, patients could have received MT or active surveillance (AS). Kaplan-Meier methods were used to estimate time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and overall survival (OS). Results: Of the 600 chart-reviewed patients included, 239 (39.8 %) received MT and 315 (52.5 %) received AS. Patients who were <65 years of age, or those with higher-stage disease or those who had received neoadjuvant treatment, were more likely to initiate MT than AS. Genetic testing rates were low across both cohorts. Median (95 % confidence interval [CI]) TTD for the MT cohort was 13.6 months (11.0, 21.2). Median (95 % CI) rwPFS was 26.9 months (21.3, not reached) and 11.3 months (9.5, 13.0) for the 1L MT and AS cohorts, respectively (p < 0.0001). OS at 36 months was 82.4 % in the 1L MT cohort and 58.0 % in the 1L AS cohort. Conclusions: This study reinforces clinical trial findings that 1L MT improves outcomes in patients with advanced OC; however, genetic testing rates and 1L MT remained low.
RESUMEN
Introduction: There is a need to understand the current treatment landscape for LA HNSCC in the real-world setting. Methods: This retrospective study assessed real-world outcomes and treatment patterns of 1,158 adult patients diagnosed with locally advanced (stage III-IVB) HNSCC initiating chemoradiotherapy (CRT) within the period January 2015 to December 2017 in a large network of US community oncology practices. Structured data were abstracted from electronic health records. Demographic, clinical and treatment characteristics were analyzed descriptively overall and stratified by index treatment (cisplatin + radiotherapy [RT], cisplatin + other chemotherapy + RT, or cetuximab + RT). Time to next treatment (TTNT) and overall survival (OS) were measured using the Kaplan-Meier method, and median duration of treatment was assessed. OS was compared across treatment cohorts using multinomial logistic regression with inverse probability treatment weighting. To identify covariates associated with OS, a multivariable adjusted Cox proportional hazard model was used. Results: This study examined 22,782 records, of which 2124 had stage III to stage IVB and no other cancers, and 1158 met all eligibility criteria. Among the treatment cohorts analyzed (cisplatin + RT, cisplatin + other chemotherapy + RT, or cetuximab + RT), cisplatin + RT was the most common concurrent chemotherapy (65.8%). Among 1158 patients, 838 (72.4%) did not initiate subsequent treatment and 139 (12.0%) died. The median TTNT and median OS were only reached by the cetuximab + RT cohort. Among patients with oropharynx primary tumor location, patients with human papilloma virus (HPV) positive status had the longest time on treatment and highest survival at 60 months. Covariates associated with improved survival were never/former tobacco use, HPV positive status, and overweight or obese body mass index. Covariates associated with poorer survival were age of 60+ years, primary tumor location of hypopharynx or oral cavity and Eastern Cooperative Oncology Group performance status score of 2+. Conclusion: These data describe real-world treatment patterns in locally advanced head and neck squamous cell cancer and sets the baseline to assess outcomes for future studies on the community oncology population.
RESUMEN
Despite the common belief among practitioners that a happy worker is a productive worker, researchers have been struggling to understand the causality between satisfaction and performance for decades. This study attempts to bring clarity to current understanding through an experiment with repeated measures of satisfaction and performance. A total of 143 participants repeatedly performed a task based on the Stroop test, with their objective performance and task satisfaction measured each time. Two different types of feedback (high/low performance) were randomly assigned to participants in order to manipulate perceived performance. The data were analyzed using a path analysis. The results support the hypothesized influence of task satisfaction on task performance and of perceived task performance on task satisfaction.
RESUMEN
Loop-mediated isothermal amplification (LAMP) is a versatile technique for detection of target DNA and RNA, enabling rapid molecular diagnostic assays with minimal equipment. The global SARS-CoV-2 pandemic has presented an urgent need for new and better diagnostic methods, with colorimetric LAMP utilized in numerous studies for SARS-CoV-2 detection. However, the sensitivity of colorimetric LAMP in early reports has been below that of the standard RT-qPCR tests, and we sought to improve performance. Here we report the use of guanidine hydrochloride and combined primer sets to increase speed and sensitivity in colorimetric LAMP, bringing this simple method up to the standards of sophisticated techniques and enabling accurate, high-throughput diagnostics.
Asunto(s)
Betacoronavirus/aislamiento & purificación , Técnicas de Laboratorio Clínico/métodos , Guanidina , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificación de Ácido Nucleico/métodos , Prueba de COVID-19 , Técnicas de Laboratorio Clínico/normas , Colorimetría , Infecciones por Coronavirus/diagnóstico , Humanos , Técnicas de Diagnóstico Molecular/normas , Técnicas de Amplificación de Ácido Nucleico/normas , Fenolsulfonftaleína , SARS-CoV-2RESUMEN
The remarkable power and specificity of enzyme catalysis rely on the dynamic alignment of the enzyme, substrates, and cofactors, yet the role of dynamics has usually been approached from the perspective of the protein. We have been using an underappreciated NMR technique, subtesla high-resolution field cycling 31P NMR relaxometry, to investigate the dynamics of the enzyme-bound substrates and cofactor on guanosine-5'-monophosphate reductase (GMPR). GMPR forms two dead end, yet catalytically competent, complexes that mimic distinct steps in the catalytic cycle: E·IMP·NADP+ undergoes a partial hydride transfer reaction, while E·GMP·NADP+ undergoes a partial deamination reaction. A different cofactor conformation is required for each partial reaction. Here we report the effects of mutations designed to perturb cofactor conformation and ammonia binding with the goal of identifying the structural features that contribute to the distinct dynamic signatures of the hydride transfer and deamination complexes. These experiments suggest that Asp129 is a central cog in a dynamic network required for both hydride transfer and deamination. In contrast, Lys77 modulates the conformation and mobility of substrates and cofactors in a reaction-specific manner. Thr105 and Tyr318 are part of a deamination-specific dynamic network that includes the 2'-OH of GMP. These residues have comparatively little effect on the dynamic properties of the hydride transfer complex. These results further illustrate the potential of high-resolution field cycling NMR relaxometry for the investigation of ligand dynamics. In addition, exchange experiments indicate that NH3/NH4+ has a high affinity for the deamination complex but a low affinity for the hydride transfer complex, suggesting that the movement of ammonia may gate the cofactor conformational change. Collectively, these experiments reinforce the view that the enzyme, substrates, and cofactor are linked in intricate, reaction-specific, dynamic networks and demonstrate that distal portions of the substrates and cofactors are critical features in these networks.
Asunto(s)
Coenzimas , GMP-Reductasa , NADP , Humanos , Amoníaco/metabolismo , Biocatálisis , Coenzimas/química , Coenzimas/metabolismo , GMP-Reductasa/genética , GMP-Reductasa/metabolismo , Guanosina Monofosfato/química , Cinética , Conformación Molecular , Mutación , NADP/química , NADP/metabolismo , Unión ProteicaRESUMEN
PURPOSE: Incident learning is a critical tool to improve patient safety. The Patient Safety and Quality Improvement Act of 2005 established essential legal protections to allow for the collection and analysis of medical incidents nationwide. METHODS AND MATERIALS: Working with a federally listed patient safety organization (PSO), the American Society for Radiation Oncology and the American Association of Physicists in Medicine established RO-ILS: Radiation Oncology Incident Learning System (RO-ILS). This paper provides an overview of the RO-ILS background, development, structure, and workflow, as well as examples of preliminary data and lessons learned. RO-ILS is actively collecting, analyzing, and reporting patient safety events. RESULTS: As of February 24, 2015, 46 institutions have signed contracts with Clarity PSO, with 33 contracts pending. Of these, 27 sites have entered 739 patient safety events into local database space, with 358 events (48%) pushed to the national database. CONCLUSIONS: To establish an optimal safety culture, radiation oncology departments should establish formal systems for incident learning that include participation in a nationwide incident learning program such as RO-ILS.
Asunto(s)
Oncología por Radiación/normas , Humanos , Administración de la SeguridadRESUMEN
Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP* as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 Å from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.
Asunto(s)
GMP-Reductasa/metabolismo , IMP Deshidrogenasa/metabolismo , Biocatálisis , Cristalografía por Rayos X , GMP-Reductasa/química , Guanosina Monofosfato/biosíntesis , Guanosina Monofosfato/química , Guanosina Monofosfato/metabolismo , Humanos , IMP Deshidrogenasa/química , Inosina Monofosfato/química , Inosina Monofosfato/metabolismo , Cinética , Modelos Moleculares , Estructura Molecular , NADP/química , NADP/metabolismo , Teoría Cuántica , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Our objectives in this study are to quantify the discharge rate of uranium (U) to the Columbia River from the Hanford Site's 300 Area and to follow that U downriver to constrain its fate. Uranium from the Hanford Site has variable isotopic composition due to nuclear industrial processes carried out at the site. This characteristic makes it possible to use high-precision isotopic measurements of U in environmental samples to identify even trace levels of contaminant U, determine its sources, and estimate discharge rates. Our data on river water samples indicate that as much as 3.2 kg/day can enter the Columbia River from the 300 Area, which is only a small fraction of the total load of dissolved natural background U carried by the Columbia River. This very low level of Hanford-derived U can be discerned, despite dilution to <1% of natural background U, 400 km downstream from the Hanford Site. These results indicate that isotopic methods can allow the amounts of U from the 300 Area of the Hanford Site entering the Columbia River to be measured accurately to ascertain whether they are an environmental concern or insignificant relative to natural uranium background in the Columbia River.
Asunto(s)
Monitoreo de Radiación/métodos , Ríos/química , Uranio/análisis , Contaminantes Radiactivos del Agua/análisis , Isótopos/análisis , Residuos Radiactivos/análisis , Uranio/química , Washingtón , Movimientos del Agua , Contaminantes Radiactivos del Agua/químicaRESUMEN
Continuous and comparable atmospheric monitoring programs to study the transport and occurrence of persistent organic pollutants (POPs) in the atmosphere of remote regions is essential to better understand the global movement of these chemicals and to evaluate the effectiveness of international control measures. Key results from four main Arctic research stations, Alert (Canada), Pallas (Finland), Storhofdi (Iceland) and Zeppelin (Svalbard/Norway), where long-term monitoring have been carried out since the early 1990s, are summarized. We have also included a discussion of main results from various Arctic satellite stations in Canada, Russia, US (Alaska) and Greenland which have been operational for shorter time periods. Using the Digital Filtration temporal trend development technique, it was found that while some POPs showed more or less consistent declines during the 1990s, this reduction is less apparent in recent years at some sites. In contrast, polybrominated diphenyl ethers (PBDEs) were still found to be increasing by 2005 at Alert with doubling times of 3.5 years in the case of deca-BDE. Levels and patterns of most POPs in Arctic air are also showing spatial variability, which is typically explained by differences in proximity to suspected key source regions and long-range atmospheric transport potentials. Furthermore, increase in worldwide usage of certain pesticides, e.g. chlorothalonil and quintozene, which are contaminated with hexachlorobenzene (HCB), may result in an increase in Arctic air concentration of HCB. The results combined also indicate that both temporal and spatial patterns of POPs in Arctic air may be affected by various processes driven by climate change, such as reduced ice cover, increasing seawater temperatures and an increase in biomass burning in boreal regions as exemplified by the data from the Zeppelin and Alert stations. Further research and continued air monitoring are needed to better understand these processes and its future impact on the Arctic environment.
Asunto(s)
Contaminantes Atmosféricos/análisis , Contaminación del Aire/estadística & datos numéricos , Atmósfera/química , Monitoreo del Ambiente , Compuestos Orgánicos/análisis , Contaminación del Aire/análisis , Regiones Árticas , Ambiente , Monitoreo del Ambiente/legislación & jurisprudencia , Regulación Gubernamental , Éteres Difenilos Halogenados/análisis , Hexaclorobenceno/análisis , Hidrocarburos Clorados/análisis , Plaguicidas/análisis , Bifenilos Policlorados/análisisRESUMEN
Collaborative coping (i.e., spouses pooling resources and problem solving jointly) may be associated with better daily mood because of heightened perceptions of efficacy in coping with stressful events. The study examined the daily processes of collaborative coping (individuals' perceptions that the spouse collaborated), perceived coping effectiveness (ratings of how well they dealt with the event), and mood (i.e., Positive and Negative Affect Scale) across 14 days in 57 older couples coping with stressors involving the husband's prostate cancer and daily life in general. In hierarchical multivariate linear models, collaborative coping was associated with more positive same-day mood for both husbands and wives and less negative mood for wives only. These associations were partially mediated by heightened perceptions of coping effectiveness. Exploratory analyses revealed that collaborative coping was more frequent among wives who performed more poorly on cognitive tests and couples who reported greater marital satisfaction and more frequently using collaboration to make decisions. The results suggest that older couples may benefit from collaborative coping in dealing with problems surrounding illness.
Asunto(s)
Adaptación Psicológica , Afecto , Composición Familiar , Acontecimientos que Cambian la Vida , Neoplasias de la Próstata/psicología , Adulto , Anciano , Anciano de 80 o más Años , Ritmo Circadiano , Conducta Cooperativa , Femenino , Humanos , Individualidad , Masculino , Matrimonio/psicología , Persona de Mediana Edad , Modelos Estadísticos , Satisfacción Personal , Inventario de Personalidad/estadística & datos numéricos , Probabilidad , Apoyo Social , Encuestas y CuestionariosRESUMEN
Lantibiotics are post-translationally modified peptide antimicrobial agents that are synthesized with an N-terminal leader sequence and a C-terminal propeptide. Their maturation involves enzymatic dehydration of Ser and Thr residues in the precursor peptide to generate unsaturated amino acids, which react intramolecularly with nearby cysteines to form cyclic thioethers termed lanthionines and methyllanthionines. The role of the leader peptide in lantibiotic biosynthesis has been subject to much speculation. In this study, mutations of conserved residues in the leader sequence of the precursor peptide for lacticin 481 (LctA) did not inhibit dehydration and cyclization by lacticin 481 synthetase (LctM) showing that not one specific residue is essential for these transformations. These amino acids may therefore be conserved in the leader sequence of class II lantibiotics to direct other biosynthetic events, such as proteolysis of the leader peptide or transport of the active compound outside the cell. However, introduction of Pro residues into the leader peptide strongly affected the efficiency of dehydration, consistent with recognition of the secondary structure of the leader peptide by the synthetase. Furthermore, the presence of a hydrophobic residue at the position of Leu-7 appears important for enzymatic processing. Based on the data in this work and previous studies, a model for the interaction of LctM with LctA is proposed. The current study also showcases the ability to prepare other lantibiotics in the class II lacticin 481 family, including nukacin ISK-1, mutacin II, and ruminococcin A using the lacticin 481 synthetase. Surprisingly, a conserved Glu located in a ring that appears conserved in many class II lantibiotics, including those not belonging to the lacticin 481 subgroup, is not essential for antimicrobial activity of lacticin 481.
Asunto(s)
Regiones no Traducidas 5'/genética , Alanina/análogos & derivados , Bacteriocinas/genética , Alanina/biosíntesis , Alanina/metabolismo , Secuencia de Aminoácidos , Aminobutiratos/metabolismo , Bacteriocinas/biosíntesis , Bacteriocinas/química , Bacteriocinas/metabolismo , Secuencia Conservada , Cartilla de ADN , Enzimas/metabolismo , Expresión Génica , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Plásmidos , Alineación de Secuencia , SulfurosRESUMEN
Lantibiotics are ribosomally synthesized and post-translationally modified peptide antibiotics. The modifications involve dehydration of Ser and Thr residues to generate dehydroalanines and dehydrobutyrines, followed by intramolecular attack of cysteines onto the newly formed dehydro amino acids to produce cyclic thioethers. LctM performs both processes during the biosynthesis of lacticin 481. Mutation of the zinc ligands Cys781 and Cys836 to alanine did not affect the dehydration activity of LctM. However, these mutations compromised cyclization activity when investigated with full length or truncated peptide substrates. Mutation of His725, another residue that is fully conserved in lantibiotic cyclases, to Asn resulted in a protein that still catalyzed dehydration of the substrate peptide and also retained cyclization activity, but at a decreased level compared to that of the wild type enzyme. Collectively, these results show that the C-terminal domain of LctM is responsible for cyclization, that the zinc ligands are critical for cyclization, and that dehydration takes place independently from the cyclization activity. Furthermore, these mutant proteins are excellent dehydratases and provide useful tools to investigate the dehydration activity as well as generate dehydrated peptides for study of the cyclization reaction by wild type LctM.
Asunto(s)
Bacteriocinas/biosíntesis , Enzimas/metabolismo , Mutación Missense , Zinc/química , Sitios de Unión , Ciclización , Enzimas/genética , Hidroliasas , Ligandos , Mutagénesis Sitio-DirigidaRESUMEN
We conducted a laboratory evaluation to assess the risk to early life stage (i.e., eyed egg to swim up) fall Chinook salmon (Oncorhynchus tshawytscha) for exposure to hexavalent chromium from a contaminated groundwater source. Local populations of fall Chinook salmon were exposed to Hanford Site source groundwater that was diluted with Columbia River water. Specific endpoints included survival, development rate, and growth. Tissue burdens of fish were also measured to estimate uptake and elimination rates of chromium. Survival, development, and growth of early life stage fall Chinook salmon were not adversely affected by extended exposures (i.e., 98 day) to hexavalent chromium ranging from 0.79 to 260 microg/l. Survival for all treatment levels and controls exceeded 98% at termination of the test. In addition, there were no differences among the mean lengths and weights of fish among all treatment groups. Whole-body concentrations of chromium in early life stage fall Chinook salmon had a typical dose-response pattern; i.e., those subjected to highest exposure concentrations and longest exposure intervals had higher tissue concentrations. Given the spatial extent of chromium concentrations at the Hanford Site, and the dynamics of the groundwater-river water interface, the current cleanup criterion of 10 microg/l chromium appear adequate to protect early life stage fall Chinook salmon. These findings, together with previous research indicate low risk to these populations.
Asunto(s)
Cromo/toxicidad , Salmón/crecimiento & desarrollo , Contaminantes Químicos del Agua/toxicidad , Animales , Ecología , Estudios de Evaluación como Asunto , Estadios del Ciclo de VidaRESUMEN
Weekly high-volume air samples were collected between 2000 and 2003 at six Arctic sites, i.e., Alert, Kinngait, and Little Fox Lake (LFL) in Canada, Point Barrow in Alaska, Valkarkai in Russia, and Zeppelin in Norway. Hexachlorocyclohexanes (HCHs) and hexachlorobenzene (HCB) were quantified in all samples. Comparison showed that alpha-HCH and HCB were homogeneously distributed in the circumpolar atmosphere and uniform throughout the seasons. However, significantly higher atmospheric concentrations of alpha-HCH and HCB and strongertemperature dependence of alpha-HCH and gamma-HCH were found at LFL in Yukon (YK), which is unique among the sites by virtue of its high altitude and low latitude, resulting in higher precipitation rates and summer temperatures. Strong temperature dependence of alpha- and gamma-HCH at this location suggests that secondary emissions, i.e., re-evaporation from surfaces, were more important at this site than others. It is hypothesized that a higher precipitation rate at LFL facilitated the transfer of alpha-HCH from the atmosphere to surface media when technical HCH was still in use worldwide. On the other hand, higher temperature at LFL enhanced reevaporation to the atmosphere after the global ban of technical HCH. In contrast to alpha-HCH and HCB, larger spatial and seasonal differences were seen for gamma-HCH (a currently used pesticide), which likely reflect the influence of different primary contaminant sources on different Arctic locations. Fugacity ratios suggest a net deposition potential of HCB from air to seawater, whereas seawater/air exchange direction of alpha-HCH varies in the circumpolar environment.
Asunto(s)
Contaminantes Atmosféricos , Atmósfera , Monitoreo del Ambiente/métodos , Hexaclorobenceno/análisis , Hexaclorociclohexano/análisis , Plaguicidas/análisis , Estaciones del Año , Regiones Árticas , Ambiente , Hidrocarburos Clorados/análisis , Control de Calidad , Agua de Mar , Propiedades de Superficie , TemperaturaRESUMEN
Lantibiotics are peptide antimicrobials containing the thioether-bridged amino acids lanthionine (Lan) and methyllanthionine (MeLan) and often the dehydrated residues dehydroalanine (Dha) and dehydrobutyrine (Dhb). While biologically advantageous, the incorporation of these residues into peptides is synthetically daunting, and their production in vivo is limited to peptides containing proteinogenic amino acids. The lacticin 481 synthetase LctM offers versatile control over the installation of dehydro amino acids and thioether rings into peptides. In vitro processing of semisynthetic substrates unrelated to the prelacticin 481 peptide demonstrated the broad substrate tolerance of LctM. Furthermore, a chemoenzymatic strategy was employed to generate novel thioether linkages by cyclization of peptidic substrates containing the nonproteinogenic cysteine analogs homocysteine and beta-homocysteine. These findings are promising with respect to the utility of LctM toward preparation of conformationally constrained peptide therapeutics.
Asunto(s)
Aminoácidos/química , Enzimas/química , Péptidos/síntesis química , Ingeniería de Proteínas/métodos , Sulfuros/química , Alanina/análogos & derivados , Alanina/síntesis química , Alanina/química , Secuencia de Aminoácidos , Bacteriocinas/química , Bacteriocinas/genética , Bacteriocinas/metabolismo , Ciclización , Deshidratación , Activación Enzimática , Enzimas/metabolismo , Conformación Molecular , Datos de Secuencia Molecular , Mutación , Péptidos/química , Sensibilidad y Especificidad , Sulfuros/síntesis químicaRESUMEN
While other research has reported on the concentrations of (129)I in the environment surrounding active nuclear fuel reprocessing facilities, there is a shortage of information regarding how the concentrations change once facilities close. At the Hanford Site, the Plutonium-Uranium Extraction (PUREX) chemical separation plant was operating between 1983 and 1990, during which time (129)I concentrations in air and milk were measured. After the cessation of chemical processing, plant emissions decreased 2.5 orders of magnitude over an 8-year period. An evaluation of (129)I and (127)I concentration data in air and milk spanning the PUREX operation and post-closure period was conducted to compare the changes in environmental levels. Measured concentrations over the monitoring period were below the levels that could result in a potential annual human dose greater than 1 mSv. There was a measurable difference in the measured air concentrations of (129)I at different distances from the source, indicating a distinct Hanford fingerprint. Correlations between stack emissions of (129)I and concentrations in air and milk indicate that atmospheric emissions were the major source of (129)I measured in environmental samples. The measured concentrations during PUREX operations were similar to observations made around a fuel reprocessing plant in Germany. After the PUREX Plant stopped operating, (129)I concentration measurements made upwind of Hanford were similar to the results from Seville, Spain.
Asunto(s)
Contaminantes Radiactivos del Aire/análisis , Radioisótopos de Yodo/análisis , Leche/química , Contaminantes Radiactivos del Aire/historia , Animales , Contaminación de Alimentos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Radioisótopos de Yodo/historia , Modelos Teóricos , Monitoreo de Radiación , Residuos Radiactivos , Medición de Riesgo , WashingtónRESUMEN
Lantibiotics are a unique class of peptide antibiotics. Recent studies of the proteins involved in the elaborate post-translational modifications of lantibiotics have revealed that these enzymes have relaxed substrate specificity. These modifications include the dehydration of serine and threonine residues followed by the intramolecular addition of cysteine thiols to the unsaturated amino acids to create an intricate polycyclic peptide. The use of peptide engineering in vivo and in vitro has allowed investigation of their biosynthetic machinery. Several members utilize a unique mode of biological action that involves the sequestration of lipid II, a crucial intermediate in peptidoglycan biosynthesis, to form pores in bacterial membranes.
Asunto(s)
Antibacterianos/biosíntesis , Antibacterianos/farmacología , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/farmacología , Péptidos/farmacología , Secuencia de Aminoácidos , Antibacterianos/química , Bacterias Gramnegativas/metabolismo , Datos de Secuencia Molecular , Biosíntesis de Péptidos , Péptidos/químicaRESUMEN
PURPOSE: To examine the impact of computerized record and verify (R&V) systems on types of radiotherapeutic error. MATERIALS AND METHODS: Radiation therapy treatment errors reported by therapists at the University of Utah between July 1, 1999 and June 30, 2000 were retrospectively reviewed. RESULTS: During a 1-year period in which 22,542 external beam radiation therapy treatments were administered, 38 treatment errors (representing 0.17% of external beam treatments administered during this period) were identified and reviewed. Nine cases (0.04% of treatments) representing four types of record and verify (R&V)-related errors were identified, in which the department's R&V system played a contributory role in the treatment error. CONCLUSIONS: The common denominator among these R&V-related errors was excessive reliance upon the computer system by therapists. R&V systems eliminate some, but not all, pathways of radiotherapeutic error. Although R&V systems have assumed a crucial role in the precise and reproducible delivery of increasingly complex radiation therapy treatments, their inability to eradicate all radiotherapeutic errors coupled with their parallel ability to facilitate certain mistakes mandates vigilance on the part of the radiation therapy team. Radiation therapy treatment procedures must preserve careful oversight of R&V functions to minimize prospects for treatment error.