The Database of Protein Disorder (DisProt) links structure and function information for intrinsically disordered proteins (IDPs). Intrinsically disordered proteins do not form a fixed ...three-dimensional structure under physiological conditions, either in their entireties or in segments or regions. We define IDP as a protein that contains at least one experimentally determined disordered region. Although lacking fixed structure, IDPs and regions carry out important biological functions, being typically involved in regulation, signaling and control. Such functions can involve high-specificity low-affinity interactions, the multiple binding of one protein to many partners and the multiple binding of many proteins to one partner. These three features are all enabled and enhanced by protein intrinsic disorder. One of the major hindrances in the study of IDPs has been the lack of organized information. DisProt was developed to enable IDP research by collecting and organizing knowledge regarding the experimental characterization and the functional associations of IDPs. In addition to being a unique source of biological information, DisProt opens doors for a plethora of bioinformatics studies. DisProt is openly available at http://www.disprot.org.
Abstract
Background
Transanal total mesorectal excision (TaTME) has been proposed as an approach in patients with mid and low rectal cancer. The TaTME procedure has been introduced in the Netherlands ...in a structured training pathway, including proctoring. This study evaluated the local recurrence rate during the implementation phase of TaTME.
Methods
Oncological outcomes of the first ten TaTME procedures in each of 12 participating centres were collected as part of an external audit of procedure implementation. Data collected from a cohort of patients treated over a prolonged period in four centres were also collected to analyse learning curve effects. The primary outcome was the presence of locoregional recurrence.
Results
The implementation cohort of 120 patients had a median follow up of 21·9 months. Short-term outcomes included a positive circumferential resection margin rate of 5·0 per cent and anastomotic leakage rate of 17 per cent. The overall local recurrence rate in the implementation cohort was 10·0 per cent (12 of 120), with a mean(s.d.) interval to recurrence of 15·2(7·0) months. Multifocal local recurrence was present in eight of 12 patients. In the prolonged cohort (266 patients), the overall recurrence rate was 5·6 per cent (4·0 per cent after excluding the first 10 procedures at each centre).
Conclusion
TaTME was associated with a multifocal local recurrence rate that may be related to suboptimal execution rather than the technique itself. Prolonged proctoring, optimization of the technique to avoid spillage, and quality control is recommended.
Graphical Abstract
During the learning curve, the transanal total mesorectal excision procedure is associated with a high multifocal local recurrence rate, which appears to be related to suboptimal execution rather than the technique, and necessitates prolonged proctoring, optimization of the technique avoiding spillage, participation in controlled clinical trials with surgical quality control, and centralization until oncological safety is demonstrated.
Graphical Abstract
Defines a learning curve
This study aimed to compare quality of life (QOL), functional outcome, body image, and cosmesis after hand-assisted laparoscopic (LRP) versus open restorative proctocolectomy (ORP). The potential ...long-term advantages of LRP over ORP remain to be determined. The most likely advantage of LRP is the superior cosmetic result. It is, however, unclear whether the size and location of incisions affect body image and QOL.
In a previously conducted randomized trial comparing LRP with ORP, 60 patients were prospectively evaluated. The primary end points were body image and cosmesis. The secondary end points were morbidity, QOL, and functional outcome. A body image questionnaire was used to evaluate body image and cosmesis. The Short Form-36 Health Survey and the Gastrointestinal Quality of Life Inventory were used to assess QOL. Body image and QOL also were assessed preoperatively.
A total of 53 patients completed the QOL and functional outcome questionnaires. There were no differences in functional outcome, morbidity, or QOL between LRP and ORP. At a median of 2.7 years after surgery, 46 patients returned the questionnaires regarding body image, cosmesis, and morbidity. The body image and cosmesis scores of female patients were significantly higher in the LRP group than in the ORP group (body image, 17.4 vs 14.9; cosmesis, 19.1 vs 13.0, respectively). The female patients in the ORP group had significantly lower body image scores than the male patients (14.9 vs 18.3).
This study is the first to show that ORP has a negative impact on body image and cosmesis as compared with LRP. Functional outcome, QOL, and morbidity are similar for the two approaches. The advantages of a long-lasting improved body image and cosmesis for this relatively young patient population may compensate for the longer operating times and higher costs, particularly for women.
Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal ...cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients.
In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients.
The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery.
NCT02371304 , registration date: February 2015.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Aims Elderly patients with colorectal carcinoma are screened with the Identification of Seniors at Risk (ISAR) questionnaire to identify frail patients. These patients are more at risk for ...mortality and morbidity and are referred to the geriatric specialist for assessment (Dutch acronym: DOG). The DOG assessment aims to preoperatively optimize the patient in order to improve postoperative outcomes. This study evaluates if the DOG assessment influences postoperative outcome after colorectal surgery. Methods Retrospective cohort and match-control study. Elderly patients who underwent elective resection between 01-01-2008 and 01-08-2013 in the Medical Centre Alkmaar were included. Patients with a positive ISAR score were referred to the geriatric specialists for DOG assessment (DOG patients). DOG assessment encompassed comprehensive geriatric assessment and interventions. Primary outcomes Mortality, delirium and length of hospital stay. Secondary outcomes: postoperative complications. Cohort comparison Cohort ISAR− (2008–2010, no ISAR questionnaire) is compared with cohort ISAR+ (2011–2013, ISAR questionnaire). Match-control comparison: DOG patients are compared with matched controls from cohort ISAR−. Results Compared to their matched controls, DOG patients were older and had a higher prevalence of certain risk factors for postoperative delirium. In both comparisons, no statistical significant differences were found between the groups in mortality and postoperative delirium. Length of stay was significantly shorter in cohort ISAR+. Conclusions While the DOG patients were significantly more at risk for postoperative complications, the DOG patients had comparable postoperative outcomes as their matched controls. We therefore conclude that the DOG assessment has a positive influence on the postoperative outcomes after colorectal surgery.
The aim of this study was to assess the functional outcome and the quality of life of laparoscopic-assisted ileal pouch-anal anastomosis compared with conventional ileal pouch-anal anastomosis. ...Further, body image and cosmesis were evaluated in both groups.
Sixteen patients who underwent a laparoscopic-assisted ileal pouch-anal anastomosis between March 1996 and September 1999 were matched with 19 patients who had a conventional ileal pouch-anal anastomosis. Patients were matched for the time period after surgery, distribution of familial adenomatous polyposis/ulcerative colitis, and one/two-stage procedure. Thirty-two patients agreed to fill out a set of questionnaires that assessed functional outcome, quality of life, body image, and cosmesis. Quality of life was measured with the Short Form 36 Health Survey questionnaire and the Gastrointestinal Quality of Life Index. The Body Image Questionnaire was used to measure patients' perceptions of and satisfaction with their own body and their attitude toward their bodily appearance (body image) and the degree of satisfaction of patients with respect to the physical appearance of the scar (cosmesis).
Patients in the conventional group were older than patients in the laparoscopic-assisted group (mean 39.2 +/- 8.4 vs. 30.6 +/- 7.1 years; P < 0.01). No differences were found in functional outcome and quality of life. Satisfaction with the cosmetic result of the scar was significantly higher in the laparoscopic-assisted group compared with the conventional group. Body image score was higher in the laparoscopic-assisted group when compared with the conventional group, although not significant.
The functional outcome and quality of life of laparoscopic-assisted ileal pouch-anal anastomosis is not different from conventional ileal pouch-anal anastomosis. In the long-term, better cosmesis is the most important advantage after laparoscopic surgery.
Arenaviruses are one of the largest families of human hemorrhagic fever viruses and are known to infect both mammals and snakes. Arenaviruses package a large (L) and small (S) genome segment in their ...virions. For segmented RNA viruses like these, novel genotypes can be generated through mutation, recombination, and reassortment. Although it is believed that an ancient recombination event led to the emergence of a new lineage of mammalian arenaviruses, neither recombination nor reassortment has been definitively documented in natural arenavirus infections. Here, we used metagenomic sequencing to survey the viral diversity present in captive arenavirus-infected snakes. From 48 infected animals, we determined the complete or near complete sequence of 210 genome segments that grouped into 23 L and 11 S genotypes. The majority of snakes were multiply infected, with up to 4 distinct S and 11 distinct L segment genotypes in individual animals. This S/L imbalance was typical: in all cases intrahost L segment genotypes outnumbered S genotypes, and a particular S segment genotype dominated in individual animals and at a population level. We corroborated sequencing results by qRT-PCR and virus isolation, and isolates replicated as ensembles in culture. Numerous instances of recombination and reassortment were detected, including recombinant segments with unusual organizations featuring 2 intergenic regions and superfluous content, which were capable of stable replication and transmission despite their atypical structures. Overall, this represents intrahost diversity of an extent and form that goes well beyond what has been observed for arenaviruses or for viruses in general. This diversity can be plausibly attributed to the captive intermingling of sub-clinically infected wild-caught snakes. Thus, beyond providing a unique opportunity to study arenavirus evolution and adaptation, these findings allow the investigation of unintended anthropogenic impacts on viral ecology, diversity, and disease potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The objectives of this study were to evaluate body image, cosmetic results, and quality of life in patients with Crohn's disease of the terminal ileum who had either laparoscopic-assisted or open ...ileocolic resection, and to determine how patients experienced the pre- and postoperative periods after both procedures.
Thirty-four patients participated: 11 patients after open resection (OR), 11 patients after laparoscopic-assisted resection (LR), and 12 patients without resection (WR). Retrospectively, the patients filled out several questionnaires pertaining to body image, hospital experiences, and quality of life. One-way analysis of variance, Student's t-tests, and Pearson's correlation were used for statistical analysis.
The cosmetic score was significantly higher in the LR than in the OR group (p < 0.01). Body image correlated strongly with cosmesis and with quality of life. The hospital experiences of the laparoscopic and open groups were similar.
Laparoscopic surgery was associated with better cosmesis than open surgery. Patients do not experience laparoscopic surgery any differently from open surgery.
Proteins can exist in a trinity of structures: the ordered state, the molten globule, and the random coil. The five following examples suggest that native protein structure can correspond to any of ...the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. (1) In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. (2) Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. (3) Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. (4) In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin’s serine/threonine phosphatase activity. Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. (5) Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding approximately 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, we will discuss 16 more proteins with native disorder. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks, and entropic bristles. Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence. The sequence–structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically >30% of eucaryotic proteins having disordered regions of length ≥ 50 consecutive residues.
Proteins participate in complex sets of interactions that represent the mechanistic foundation for much of the physiology and function of the cell. These protein-protein interactions are organized ...into exquisitely complex networks. The architecture of protein-protein interaction networks was recently proposed to be scale-free, with most of the proteins having only one or two connections but with relatively fewer 'hubs' possessing tens, hundreds or more links. The high level of hub connectivity must somehow be reflected in protein structure. What structural quality of hub proteins enables them to interact with large numbers of diverse targets? One possibility would be to employ binding regions that have the ability to bind multiple, structurally diverse partners. This trait can be imparted by the incorporation of intrinsic disorder in one or both partners. To illustrate the value of such contributions, this review examines the roles of intrinsic disorder in protein network architecture. We show that there are three general ways that intrinsic disorder can contribute: First, intrinsic disorder can serve as the structural basis for hub protein promiscuity; secondly, intrinsically disordered proteins can bind to structured hub proteins; and thirdly, intrinsic disorder can provide flexible linkers between functional domains with the linkers enabling mechanisms that facilitate binding diversity. An important research direction will be to determine what fraction of protein-protein interaction in regulatory networks relies on intrinsic disorder.
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