Chitosan oligosaccharides (COS) are attractive active molecules for biomedical applications. Currently, the prohibitively high cost of producing fully defined COS hampers extensive studies on their biological activity and restricts their use in various industries. Thus, cost-effective production of pure COS is of major importance. In this report, chitosanase from Bacillus subtilis MY002 (CsnMY002) was prepared for COS production. The structure of apo CsnMY002 displayed an unexpected tunnel-like substrate-binding site and the structure of the CsnMY002_E19A/(GlcN)6 complex highlighted the "4 + 2″ splitting of hexaglucosamine even though the "3 + 3″ splitting is also observed in the TLC analysis of the enzyme products for hexaglucosamine. Structure based rational design was performed to generate mutants for chitobiose production. The CsnMY002_G21 K mutant produced chitobiose with a relative content > 87 % from chitosan with a low degree of acetylation, and 50.65 mg chitobiose with a purity > 98 % was prepared from 100 mg chitosan. The results provide insight on the catalytic mechanism of chitosanase and underpin future biomedical applications of pure chitobiose. In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide). This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR. Overall, 63 patients received treatment (abiraterone/prednisone combination, n= 22; enzalutamide combination, n= 22; radium-223 monotherapy, n= 19). Median treatment duration (first to last dose of any study treatmereatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication. Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m , twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size 50 patients) for each cohort. Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). check details DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P= 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P= 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT.FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT. To develop a training program in Motivational Interviewing for Family Physicians and assess the impact. Multicenter, double blind and randomized clinical essay, with 2arms, Experimental (EG) and Control (CG) of Family Physicians with a follow up of 12 months. 32 Primary Healthcare Centers. 54 physicians (CG=28, EG=26). Training Program MOTIVA in ME with an initial presential course (16h), followed by online activities during 12months, and presential meetings (Problem BasedInterviewing with expert feedback). Communicative skills in MI were assessed based on video-recordings (VR) with the EVEM 2.0 scale by peer reviewers. 236 VR with standardized patients and 96 VR with real patients. Average results in EVEM scale (up to 56 points) at the beginning of the study were EG=21.27 (CI 95% 15.8-26.7) and CG=20.23 (CI95% 16.4-23.9) with no differences between both groups (P=.79). After the training, EG punctuation increased by 13.89 points (P<.001), average 35.16 (CI 95% 29.8-40.6). Real patients' VR in EG over a 12 month period keep their MI skills with an average of 36.9 points (CI 95% 30.3-43.6) versus CG 15.9 points (CI 95% 9.8-22.0). Once ended the MOTIVA Training Program, the EG maintains the acquired skills final average EG=37.6 (CI 95% 33.2-41.1) versus CG=24.3 (CI95% 19.0-29.2) (P<.001). The MOTIVA Training Program improves Motivational Interviewing skills, significatively improving after a presential course and sequential keep-alive activities. The effectiveness of the Program has been proven in the Third and Fourth steps of Miller's Pyramid.The MOTIVA Training Program improves Motivational Interviewing skills, significatively improving after a presential course and sequential keep-alive activities. The effectiveness of the Program has been proven in the Third and Fourth steps of Miller's Pyramid.