Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a ...disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.
Recently it has become commonplace to use population size to explain patterns in the Paleolithic archaeological record. Several modeling studies support the idea that population size can affect ...cultural evolution, but the results of empirical studies are ambiguous. Here we report a study that used tool kit data from recent hunter-gatherers, in conjunction with correlation analysis and a global sample, a continental sample, and a regional sample. The results of the analyses do not support the hypothesis. Population size was correlated with some tool kit variables in the global sample, but these relationships disappeared when two factors that have previously been found to affect hunter-gatherer tool kits—risk of resource failure and mobility—were controlled for. Population size was not correlated with the tool kit variables in the other samples. The regression analyses also did not support the population size hypothesis. Together, these results challenge the use of population size to explain patterns in the Paleolithic archaeological record. Population size may explain some of the patterns in question, but this needs to be demonstrated through tests in which the population size hypothesis is explicitly pitted against competing hypotheses, such as adaptation to shifting ecological conditions.
Silica‐supported AgNO3 (AgNO3–SiO2) catalyzes the dearomatizing spirocyclization of alkyne‐tethered aromatics far more effectively than the analogous unsupported reagent; in many cases, reactions ...which fail using unsupported AgNO3 proceed effectively with AgNO3–SiO2. Mechanistic studies indicate that this is a consequence of silver nanoparticle formation on the silica surface combined with a synergistic effect caused by the silica support itself. The remarkable ease with which the reagent can be prepared and used is likely to be of much synthetic importance, in particular, by making nanoparticle catalysis more accessible to non‐specialists.
Nanoparticle catalysis: Silica‐supported AgNO3 catalyzes the dearomatizing spirocyclization of alkyne‐tethered aromatics far more effectively than the analogous unsupported reagent. Mechanistic studies indicate that this is a consequence of silver nanoparticle formation on the silica surface combined with a synergistic effect caused by the silica support itself.
The clinical significance of serrated polyps Huang, Christopher S; Farraye, Francis A; Yang, Shi ...
The American journal of gastroenterology,
02/2011, Letnik:
106, Številka:
2
Journal Article
Recenzirano
Colorectal cancer (CRC) is a heterogeneous disorder than arises via multiple distinct pathways, such as the serrated pathway, in which serrated polyps (including variants of hyperplastic polyps) are ...the precursor lesions. Approximately 15-20% of all CRCs arise via the serrated pathway, and these serrated carcinomas are clinically, morphologically, and molecularly distinct from conventional CRCs. The prevention of serrated carcinomas represents an important clinical challenge. Gastroenterologists need to recognize and remove potential precursor lesions and implement a post-polypectomy surveillance program when appropriate. This article focuses on the characteristics and significance of clinically relevant serrated polyps and addresses implications for CRC prevention practices.
Indolyl α‐diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of catalyst and reaction conditions. A range of catalysts were used, including complexes ...of RhII, PdII, and CuII, as well as SiO2, to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.
Pick a catalyst: Indolyl α‐diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of the catalyst and reaction conditions. A range of catalysts were used, including complexes of RhII, PdII, and CuII as well as SiO2, to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.
We use the concept of niche construction—the process whereby individuals, through their activities, interactions, and choices, modify their own and each other's environments—as an example of how ...biological evolution and cultural evolution interacted to form an integrative foundation of modern organizational leadership. Resulting adaptations are formal structures that facilitate coordination of large, postagrarian organizational networks. We provide three propositions explaining how leadership processes evolve over time within and between organizations in order to solve specific coordination problems. We highlight the balancing act between self-interests and group interests in organizations and show how leadership must regulate this tension to maintain organizational fitness. We conclude with predictions about the future evolution of leadership in organizations.
When physicians consider which analgesia to use postsurgery, the primary goal is to relieve pain with minimal adverse side effects. Bupivacaine, a commonly used analgesic, has been formulated into an ...aqueous suspension of multivesicular liposomes that provide long-lasting analgesia for up to 72 hours, while avoiding the adverse side effects of opioids. The increased efficacy of liposomal extended-release bupivacaine, compared to bupivacaine hydrochloride, has promoted its usage in a variety of surgeries including hemorrhoidectomy, bunionectomy, inguinal hernia repair, total knee arthroplasty, and augmentation mammoplasty. However, like other bupivacaine formulations, the liposomal extended-release bupivacaine does have some side effects. In this brief review, we provide an update of the current knowledge in the use of bupivacaine for postsurgical analgesia.
To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high ...circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses.
Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m(2) for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m(2).
Toxicity with the first dose (375 mg/m(2)) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m(2) was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P <.001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m(2), 43% for those treated at 1,000 to 1,500 mg/m(2), and 75% for those treated at the highest dose of 2,250 mg/m(2) (P =.007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon.
Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.
Research has shown that post-primary Irish youth are insufficiently active and fail to reach a level of proficiency across basic movement skills. The purpose of the current research was to gather ...cross-sectional baseline data on Irish adolescent youth, specifically the prevalence of movement skills and patterns, in order to generate an overall perspective of movement within the first three years (Junior Certificate level) of post-primary education.
Data were collected on adolescents (N = 181; mean age: 14.42 ± 0.98 years), attending two, mixed-gender schools. Data collection included 10 fundamental movement skills (FMS) and the seven tests within the Functional Movement Screen (FMS™). The data set was analysed using the Statistical Package for Social Sciences (SPSS) version 20.0 for Windows.
Overall, levels of actual mastery within fundamental and functional movement were low. There were statistically significant age-related differences observed, with a progressive decline as age increased in both the object control (
= 0.002) FMS sub-domain, and the in-line lunge (
= 0.048) test of the FMS™.
In summary, we found emerging evidence that school year group is significantly associated with mastery of movement skills and patterns. Results from the current study suggest that developing a specifically tailored movement-oriented intervention would be a strategic step towards improving the low levels of adolescent fundamental and functional movement proficiency.
Detailed structural comparisons of sperm-specific glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) and the somatic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme should ...facilitate the identification of selective GAPDHS inhibitors for contraceptive development.
This study identified a small-molecule GAPDHS inhibitor with micromolar potency and >10-fold selectivity that exerts the expected inhibitory effects on sperm glycolysis and motility.
Glycolytic ATP production is required for sperm motility and male fertility in many mammalian species. Selective inhibition of GAPDHS, one of the glycolytic isozymes with restricted expression during spermatogenesis, is a potential strategy for the development of a non-hormonal contraceptive that directly blocks sperm function.
Homology modeling and x-ray crystallography were used to identify structural features that are conserved in GAPDHS orthologs in mouse and human sperm, but distinct from the GAPDH orthologs present in somatic tissues. We identified three binding pockets surrounding the substrate and cofactor in these isozymes and conducted a virtual screen to identify small-molecule compounds predicted to bind more tightly to GAPDHS than to GAPDH. Following the production of recombinant human and mouse GAPDHS, candidate compounds were tested in dose-response enzyme assays to identify inhibitors that blocked the activity of GAPDHS more effectively than GAPDH. The effects of a selective inhibitor on the motility of mouse and human sperm were monitored by computer-assisted sperm analysis, and sperm lactate production was measured to assess inhibition of glycolysis in the target cell.
Our studies produced the first apoenzyme crystal structures for human and mouse GAPDHS and a 1.73 Å crystal structure for NAD(+)-bound human GAPDHS, facilitating the identification of unique structural features of this sperm isozyme. In dose-response assays T0501_7749 inhibited human GAPDHS with an IC50 of 1.2 μM compared with an IC50 of 38.5 μM for the somatic isozyme. This compound caused significant reductions in mouse sperm lactate production (P= 0.017 for 100 μM T0501_7749 versus control) and in the percentage of motile mouse and human sperm (P values from <0.05 to <0.0001, depending on incubation conditions).
The chemical properties of T0501_7749, including limited solubility and nonspecific protein binding, are not optimal for drug development.
This study provides proof-of-principle evidence that GAPDHS can be selectively inhibited, causing significant reductions in sperm glycolysis and motility. These results highlight the utility of structure-based drug design and support further exploration of GAPDHS, and perhaps other sperm-specific isozymes in the glycolytic pathway, as contraceptive targets.
None. Coordinates and data files for three GAPDHS crystal structures were deposited in the RCSB Protein Data Bank (http://www.rcsb.org).
This work was supported by grants from the National Institutes of Health (NIH), USA, including U01 HD060481 and cooperative agreement U54 HD35041 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and TW/HD00627 from the NIH Fogarty International Center. Additional support was provided by subproject CIG-05-109 from CICCR, a program of CONRAD, Eastern Virginia Medical School, USA. There are no conflicts of interest.
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