Correlating biological activity to thermo-structural analysis of the interaction of CTX with synthetic models of macrophage membranes

The important pharmacological actions of Crotoxin (CTX) on macrophages, the main toxin in the venom of Crotalus durissus terrificus, and its important participation in the control of different pathophysiological processes, have been demonstrated. The biological activities performed by macrophages are related to signaling mediated by receptors expressed on the membrane surface of these cells or opening and closing of ion channels, generation of membrane curvature and pore formation. In the present work, the interaction of the CTX complex with the cell membrane of macrophages is studied, both using biological cells and synthetic lipid membranes to monitor structural alterations induced by the protein. Here we show that CTX can penetrate THP-1 cells and induce pores only in anionic lipid model membranes, suggesting that a possible access pathway for CTX to the cell is via lipids with anionic polar heads. Considering that the selectivity of the lipid composition varies in different tissues and organs of the human body, the thermostructural studies presented here are extremely important to open new investigations on the biological activities of CTX in different biological systems.

EP.TU.465Role of CT scan as initial investigation in colorectal rapid access patients

Background We looked into CT colonoscopies and CT abdomen and pelvis which were booked as initial investigation in patients referred via the colorectal rapid access pathway. These tests were directly booked following the referral after a nurse led triage. As per our colorectal straight to test protocol (STT) any patients over the age of 75 or unfit individuals will have a CT colonoscopy (virtual colonoscopy) instead of colonoscopy. CT trunk was used during COVID pandemic as the initial investigation when the aerosol generating procedures were stopped. CT trunks are also the initial investigation as per the STT protocol when patients are referred with suspected abdominal mass, weight loss or abdominal pain. Methods Retrospective analysis of prospective electronic data base of colorectal STT referrals from Feb 2020 to end of October 2020. Results Conclusion CT colonoscopies and CT trunks form part of initial diagnostic tool in the colorectal rapid access patients. They are particularly useful in high risk patients who cannot tolerate colonoscopy. These investigations complement the lower GI endoscopy. These scans also identify non-colorectal malignancies and retroperitoneal pathology such as AAA.CT trunks were useful tools during COVID 19 Pandemic.

SP10.1.6 Benefit of Two week colorectal cancer referrals of patients who had colonic imaging within the last 5 years: do they improve the colorectal cancer outcome?

Purpose There has been a significant rise in the number of colorectal rapid access referrals. These referral results in additional demand for hospital services as well as delays assessment and management of other patients. We analyzed the outcome of colorectal fast tract clinic re- referrals on bowel cancer outcome in patients with recent colonic imaging. Methods We retrospectively analyzed 1000 consecutive colorectal rapid access pathway referrals in 2019.Patients with complete colonic imaging within the preceding 5 years were included. We assessed their clinical outcome and colonic imaging when performed. Results In total, 82 (8.2%) patients out of 1000 met the selection criteria. Among these 12 patients (14%) did not need any further colonic investigations. A further 12 patients (14%) were already on the colorectal surveillance program, including a patient with recently diagnosed rectal cancer. Hence 24 patients (29.2%) referral was not indicated. 58 patients had further colonic imaging in the form of colonoscopy or virtual colonoscopy following clinic consultation. 32 (55.17%) of them had normal colonic imaging. 14 patients (24.1%) were identified with colorectal polyps with only one identified as tubular adenoma. The remaining 12 patients had non neoplastic pathology. Conclusion No new significant colorectal pathology was identified in this group of patients. We suggest that symptomatic patients who had complete colonic imaging within 5 years be referred to routine colorectal clinic in order to make the colorectal rapid access referral pathway more effective especially during these unprecedented times.

EP.WE.913Evaluation of upper GI cancer diagnosis in suspected patients referred for OGD directly by GP vs Two Week Referral pathways

Aim To assess whether the new direct pathway (requested by GP) has improved OGD accessibility and time of diagnosis for patients with suspected UGI cancer. The new system aimed to bypass a formal referral to UGI clinic. Methodology Retrospective study, compared two groups of patients (total 329). Group A (173 patients, TWW referral to UGI clinic who had endoscopy between March and May 2017), and Group B (156 patients, Direct access pathway by the GP to have the endoscopy between March and May 2018). inclusion criteria includes patients referred directly by the GP between March and May 2018, TWW patients referred March-May 2017. Patients who had OGD with suspected diagnosis other than UGI cancer were excluded. Data was compared in terms of gender, age, interval time between referral and OGD, and cancer findings. Findings Time between presentation and diagnosis in patients referred via Direct Access pathway was shown to be significantly shorter compared to patients admitted via TWW. The difference was 7 days in favor of the Direct Access pathway which was statistically significant (p value 0.001). Recommendations Direct access pathway has decreased the waiting time, expedited the management, potential money saved, more available clinic space and less administrative work.

SP4.1.10 Colorectal Cancer Services During the First Wave of the COVID-19 Pandemic

Aims During the first wave of the COVID-19 pandemic, UK health services ceased National Bowel Cancer Screening programme and non-emergency diagnostic services were halted. This retrospective study evaluated the colorectal cancer (CRC) service at a district general hospital during that period by comparing the CRC services from 31/03/2020 to 28/06/2020 to services offered during the same 3-month period of the previous year. Methods 65 patients were included in the study (47 from 2019 and 18 from 2020). Demographics, referral modes, treatment aims and Dukes cancer staging at diagnosis were compared. À2 and Fisher’s exact tests were used. Results There was a 61.7% decrease in the volume of patients managed and 65.7% reduction in operations relative to the previous year. The mean age(years) of 66.6 (S.D 14.1) during the pandemic was lower than the average during the non-COVID year (75.5(S.D 13)) but gender distribution was similar. COVID-year referrals originated from rapid access pathway (61%), emergency (28%), routine referrals (11%), screening (0%) compared to 56%, 21%, 21%, and 2% respectively during the non-COVID period. Dukes staging varied with Dukes D doubling (39% vs 17%) and no Dukes A (6% in 2019) during the pandemic. The treatment goal during the pandemic was palliative in 44% vs 32% in the other group. Conclusion Cessation of non-emergency diagnostic pathways that support identification of early disease contributed to diagnostic delays with increased proportion of palliative/Dukes D disease. Normal CRC services should be sustained during future pandemics to avoid missing curable disease.

Infrared thermography as an access pathway for individuals with severe motor impairments

Infrared thermography as an access pathway for individuals with severe motor impairments

Infrared thermography as an access pathway for individuals with severe motor impairments

Infrared thermography as an access pathway for individuals with severe motor impairments

Two ligand-binding sites in CO-reducing V nitrogenase reveal a general mechanistic principle

Besides its role in biological nitrogen fixation, vanadium-containing nitrogenase also reduces carbon monoxide (CO) to hydrocarbons, in analogy to the industrial Fischer-Tropsch process. The protein yields 93% of ethylene (C2H4), implying a C–C coupling step that mandates the simultaneous binding of two CO at the active site FeV cofactor. Spectroscopic data indicated multiple CO binding events, but structural analyses of Mo and V nitrogenase only confirmed a single site. Here, we report the structure of a two CO-bound state of V nitrogenase at 1.05 Å resolution, with one μ-bridging and one terminal CO molecule. This additional, specific ligand binding site suggests a mechanistic route for CO reduction and hydrocarbon formation, as well as a second access pathway for protons required during the reaction. Moreover, carbonyls are strong-field ligands that are chemically similar to mechanistically relevant hydrides that may be formed and used in a fully analogous fashion.

Ubiquinone Binding and Reduction by Complex I—Open Questions and Mechanistic Implications

NADH: ubiquinone oxidoreductase (complex I) is the first enzyme complex of the respiratory chain. Complex I is a redox-driven proton pump that contributes to the proton motive force that drives ATP synthase. The structure of complex I has been analyzed by x-ray crystallography and electron cryo-microscopy and is now well-described. The ubiquinone (Q) reduction site of complex I is buried in the peripheral arm and a tunnel-like structure is thought to provide access for the hydrophobic substrate from the membrane. Several intermediate binding positions for Q in the tunnel were identified in molecular simulations. Structural data showed the binding of native Q molecules and short chain analogs and inhibitors in the access pathway and in the Q reduction site, respectively. We here review the current knowledge on the interaction of complex I with Q and discuss recent hypothetical models for the coupling mechanism.