Post-polypectomy surveillance interval and advanced neoplasia detection rates: a multicenter, retrospective cohort study

Background Longer post-polypectomy surveillance intervals are associated with increased colorectal neoplasia detection at surveillance in some studies. We investigated this association to inform optimal surveillance intervals. Methods Patients who underwent colonoscopy and post-polypectomy surveillance at 17 UK hospitals were classified as low/high risk by baseline findings. We compared detection rates of advanced adenomas (≥ 10 mm, tubulovillous/villous, high grade dysplasia), high risk findings (HRFs: ≥ 2 serrated polyps/[adenomas] of which ≥ 1 is ≥ 10 mm or has [high grade] dysplasia; ≥ 5 serrated polyps/adenomas; or ≥ 1 nonpedunculated polyp ≥ 20 mm), or colorectal cancer (CRC) at surveillance colonoscopy by surveillance interval (< 18 months, 2, 3, 4, 5, 6 years). Risk ratios (RRs) were estimated using multivariable regression. Results Of 11 214 patients, 7216 (64 %) were low risk and 3998 (36 %) were high risk. Among low risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 7.8 %, 3.7 %, and 1.1 %, respectively. Advanced adenoma detection increased with increasing surveillance interval, reaching 9.8 % with a 6-year interval (P trend < 0.001). Among high risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 15.3 %, 10.0 %, and 1.5 %, respectively. Advanced adenoma and CRC detection rates (P trends < 0.001) increased with increasing surveillance interval; RRs (95 % confidence intervals) for CRC were 1.54 (0.68–3.48), 4.44 (1.95–10.08), and 5.80 (2.51–13.40) with 3-, 4-, and 5-year intervals, respectively, versus an interval of < 18 months. Conclusions Metachronous neoplasia was uncommon among low risk patients, even with long surveillance intervals, supporting recommendations for no surveillance in these patients. For high risk patients, a 3-year surveillance interval would ensure timely CRC detection

Combining Feature Selection and Integration—A Neural Model for MT Motion Selectivity

Background: The computation of pattern motion in visual area MT based on motion input from area V1 has been investigated in many experiments and models attempting to replicate the main mechanisms. Two different core conceptual approaches were developed to explain the findings. In integrationist models the key mechanism to achieve pattern selectivity is the nonlinear integration of V1 motion activity. In contrast, selectionist models focus on the motion computation at positions with 2D features. Methodology/Principal Findings: Recent experiments revealed that neither of the two concepts alone is sufficient to explain all experimental data and that most of the existing models cannot account for the complex behaviour found. MT pattern selectivity changes over time for stimuli like type II plaids from vector average to the direction computed with an intersection of constraint rule or by feature tracking. Also, the spatial arrangement of the stimulus within the receptive field of a MT cell plays a crucial role. We propose a recurrent neural model showing how feature integration and selection can be combined into one common architecture to explain these findings. The key features of the model are the computation of 1D and 2D motion in model area V1 subpopulations that are integrated in model MT cells using feedforward and feedback processing. Our results are also in line with findings concerning the solution of the aperture problem. Conclusions/Significance: We propose a new neural model for MT pattern computation and motion disambiguation that i

Colonoscopy surveillance following adenoma removal to reduce the risk of colorectal cancer: a retrospective cohort study

Background Colonoscopy surveillance is recommended for some patients post polypectomy. The 2002 UK surveillance guidelines classify post-polypectomy patients into low, intermediate and high risk, and recommend different strategies for each classification. Limited evidence supports these guidelines. Objectives To examine, for each risk group, long-term colorectal cancer incidence by baseline characteristics and the number of surveillance visits; the effects of interval length on detection rates of advanced adenomas and colorectal cancer at first surveillance; and the cost-effectiveness of surveillance compared with no surveillance. Design A retrospective cohort study and economic evaluation. Setting Seventeen NHS hospitals. Participants Patients with a colonoscopy and at least one adenoma at baseline. Main outcome measures Long-term colorectal cancer incidence after baseline and detection rates of advanced adenomas and colorectal cancer at first surveillance. Data sources Hospital databases, NHS Digital, the Office for National Statistics, National Services Scotland and Public Health England. Methods Cox regression was used to compare colorectal cancer incidence in the presence and absence of surveillance and to identify colorectal cancer risk factors. Risk factors were used to stratify risk groups into higher- and lower-risk subgroups. We examined detection rates of advanced adenomas and colorectal cancer at first surveillance by interval length. Cost-effectiveness of surveillance compared with no surveillance was evaluated in terms of incremental costs per colorectal cancer prevented and per quality-adjusted life-year gained. Results Our study included 28,972 patients, of whom 14,401 (50%), 11,852 (41%) and 2719 (9%) were classed as low, intermediate and high risk, respectively. The median follow-up time was 9.3 years. Colorectal cancer incidence was 140, 221 and 366 per 100,000 person-years among low-, intermediate- and high-risk patients, respectively. Attendance at one surveillance visit was associated with reduced colorectal cancer incidence among low-, intermediate- and high-risk patients [hazard ratios were 0.56 (95% confidence interval 0.39 to 0.80), 0.59 (95% confidence interval 0.43 to 0.81) and 0.49 (95% confidence interval 0.29 to 0.82), respectively]. Compared with the general population, colorectal cancer incidence without surveillance was similar among low-risk patients and higher among high-risk patients [standardised incidence ratios were 0.86 (95% confidence interval 0.73 to 1.02) and 1.91 (95% confidence interval 1.39 to 2.56), respectively]. For intermediate-risk patients, standardised incidence ratios differed for the lower- (0.70, 95% confidence interval 0.48 to 0.99) and higher-risk (1.46, 95% confidence interval 1.19 to 1.78) subgroups. In each risk group, incremental costs per colorectal cancer prevented and per quality-adjusted life-year gained with surveillance were lower for the higher-risk subgroup than for the lower-risk subgroup. Incremental costs per quality-adjusted life-year gained were lowest for the higher-risk subgroup of high-risk patients at £7821. Limitations The observational design means that we cannot assume that surveillance caused the reductions in cancer incidence. The fact that some cancer staging data were missing places uncertainty on our cost-effectiveness estimates. Conclusions Surveillance was associated with reduced colorectal cancer incidence in all risk groups. However, in low-risk patients and the lower-risk subgroup of intermediate-risk patients, colorectal cancer incidence was no higher than in the general population without surveillance, indicating that surveillance might not be necessary. Surveillance was most cost-effective for the higher-risk subgroup of high-risk patients

An influenza virus-inspired polymer system for the timed release of siRNA

Small interfering RNA silences specific genes by interfering with mRNA translation, and acts to modulate or inhibit specific biological pathways; a therapy that holds great promise in the cure of many diseases. However, the naked small interfering RNA is susceptible to degradation by plasma and tissue nucleases and due to its negative charge unable to cross the cell membrane. Here we report a new polymer carrier designed to mimic the influenza virus escape mechanism from the endosome, followed by a timed release of the small interfering RNA in the cytosol through a self-catalyzed polymer degradation process. Our polymer changes to a negatively charged and non-toxic polymer after the release of small interfering RNA, presenting potential for multiple repeat doses and long-term treatment of diseases

Systematic review of factors influencing patient and practitioner delay in diagnosis of upper gastrointestinal cancer

As knowledge on the causation of cancers advances and new treatments are developed, early recognition and accurate diagnosis becomes increasingly important. This review focused on identifying factors influencing patient and primary care practitioner delay for upper gastrointestinal cancer. A systematic methodology was applied, including extensive searches of the literature published from 1970 to 2003, systematic data extraction, quality assessment and narrative data synthesis. Included studies were those evaluating factors associated with the time interval between a patient first noticing a cancer symptom and presenting to primary care, between a patient first presenting to primary care and being referred to secondary care, or describing an intervention designed to reduce those intervals. Twenty-five studies were included in the review. Studies reporting delay intervals demonstrated that the patient phase of delay was greater than the practitioner phase, whilst patient-related research suggests that recognition of symptom seriousness is more important than recognition of the presence of the symptom. The main factors related to practitioner delay were misdiagnosis, application and interpretation of tests, and the confounding effect of existing disease. Greater understanding of patient factors is required, along with evaluation of interventions to ensure appropriate diagnosis, examination and investigation

The Structural Complexity of the Human BORIS Gene in Gametogenesis and Cancer

BORIS/CTCFL is a paralogue of CTCF, the major epigenetic regulator of vertebrate genomes. BORIS is normally expressed only in germ cells but is aberrantly activated in numerous cancers. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions.Here we show that BORIS is expressed as 23 isoforms in germline and cancer cells. The isoforms are comprised of alternative N- and C-termini combined with varying numbers of zinc fingers (ZF) in the DNA binding domain. The patterns of BORIS isoform expression are distinct in germ and cancer cells. Isoform expression is activated by downregulation of CTCF, upregulated by reduction in CpG methylation caused by inactivation of DNMT1 or DNMT3b, and repressed by activation of p53. Studies of ectopically expressed isoforms showed that all are translated and localized to the nucleus. Using the testis-specific cerebroside sulfotransferase (CST) promoter and the IGF2/H19 imprinting control region (ICR), it was shown that binding of BORIS isoforms to DNA targets in vitro is methylation-sensitive and depends on the number and specific composition of ZF. The ability to bind target DNA and the presence of a specific long amino terminus (N258) in different isoforms are necessary and sufficient to activate CST transcription. Comparative sequence analyses revealed an evolutionary burst in mammals with strong conservation of BORIS isoproteins among primates.The extensive repertoire of spliced BORIS variants in humans that confer distinct DNA binding and transcriptional activation properties, and their differential patterns of expression among germ cells and neoplastic cells suggest that the gene is involved in a range of functionally important aspects of both normal gametogenesis and cancer development. In addition, a burst in isoform diversification may be evolutionarily tied to unique aspects of primate speciation

Cellular Cytoskeleton Dynamics Modulates Non-Viral Gene Delivery through RhoGTPases

Although it is well accepted that the constituents of the cellular microenvironment modulate a myriad of cellular processes, including cell morphology, cytoskeletal dynamics and uptake pathways, the underlying mechanism of how these pathways influence non-viral gene transfer have not been studied. Transgene expression is increased on fibronectin (Fn) coated surfaces as a consequence of increased proliferation, cell spreading and active engagement of clathrin endocytosis pathway. RhoGTPases mediate the crosstalk between the cell and Fn, and regulate cellular processes involving filamentous actin, in-response to cellular interaction with Fn. Here the role of RhoGTPases specifically Rho, Rac and Cdc42 in modulation of non-viral gene transfer in mouse mesenchymal stem (mMSCs) plated in a fibronectin microenvironment was studied. More than 90% decrease in transgene expression was observed after inactivation of RhoGTPases using difficile toxin B (TcdB) and C3 transferase. Expression of dominant negative RhoA (RhoAT19N), Rac1(Rac1T17N) and Cdc42 (Cdc42T17N) also significantly reduced polyplex uptake and transgene expression. Interactions of cells with Fn lead to activation of RhoGTPases. However, further activation of RhoA, Rac1 and Cdc42 by expression of constitutively active genes (RhoAQ63L, Rac1Q61L and Cdc42Q61L) did not further enhance transgene expression in mMSCs, when plated on Fn. In contrast, activation of RhoA, Rac1 and Cdc42 by expression of constitutively active genes for cells plated on collagen I, which by itself did not increase RhoGTPase activation, resulted in enhanced transgene expression. Our study shows that RhoGTPases regulate internalization and effective intracellular processing of polyplexes that results in efficient gene transfer

Structure and function of the Ts2631 endolysin of <i>Thermus scotoductus</i> phage vB_Tsc2631 with unique N-terminal extension used for peptidoglycan binding

Abstract To escape from hosts after completing their life cycle, bacteriophages often use endolysins, which degrade bacterial peptidoglycan. While mesophilic phages have been extensively studied, their thermophilic counterparts are not well characterized. Here, we present a detailed analysis of the structure and function of Ts2631 endolysin from thermophilic phage vB_Tsc2631, which is a zinc-dependent amidase. The active site of Ts2631 consists of His30, Tyr58, His131 and Cys139, which are involved in Zn2+ coordination and catalysis. We found that the active site residues are necessary for lysis yet not crucial for peptidoglycan binding. To elucidate residues involved in the enzyme interaction with peptidoglycan, we tested single-residue substitution variants and identified Tyr60 and Lys70 as essential residues. Moreover, substitution of Cys80, abrogating disulfide bridge formation, inactivates Ts2631, as do substitutions of His31, Thr32 and Asn85 residues. The endolysin contains a positively charged N-terminal extension of 20 residues that can protrude from the remainder of the enzyme and is crucial for peptidoglycan binding. We show that the deletion of 20 residues from the N-terminus abolished the bacteriolytic activity of the enzyme. Because Ts2631 exhibits intrinsic antibacterial activity and unusual thermal stability, it is perfectly suited as a scaffold for the development of antimicrobial agents

Hydrophilic interaction liquid chromatography (HILIC) in proteomics

In proteomics, nanoflow multidimensional chromatography is now the gold standard for the separation of complex mixtures of peptides as generated by in-solution digestion of whole-cell lysates. Ideally, the different stationary phases used in multidimensional chromatography should provide orthogonal separation characteristics. For this reason, the combination of strong cation exchange chromatography (SCX) and reversed-phase (RP) chromatography is the most widely used combination for the separation of peptides. Here, we review the potential of hydrophilic interaction liquid chromatography (HILIC) as a separation tool in the multidimensional separation of peptides in proteomics applications. Recent work has revealed that HILIC may provide an excellent alternative to SCX, possessing several advantages in the area of separation power and targeted analysis of protein post-translational modifications

Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study.

OBJECTIVE: The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services. DESIGN: Intermediate-risk patients (60-72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012-December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance. RESULTS: 74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively. CONCLUSIONS: Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%-40% of CRCs and 40%-70% of AAs. TRIAL REGISTRATION NUMBER: ISRCTN18040196; Results