Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain.

The self-assembly of micellar structures from diblock polymers that contain hydrophilic and hydrophobic domains has been of great interest for the encapsulation of drugs and other hydrophobic molecules. While most commercially used surfactants are derived from hydrocarbon sources, there have been recent efforts to replace these with biodegradable, nontoxic, biologically synthesized alternatives. Previous examples have primarily examined naturally occurring self-assembling proteins, such as silk and elastin-like sequences. Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values in the low micromolar range, 3 orders of magnitude lower than the CMC of commonly used surfactant sodium dodecyl sulfate (SDS). The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications. Furthermore, the inherent flexibility in the design of these protein sequences enables the encoding of additional functionalities for many future applications. Overall, this work represents a new biomolecular alternative to traditional surfactants that are based on nonrenewable and poorly biodegradable hydrocarbon sources.

Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified. METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software. RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes. CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Almost Psychiatry: The Impact of Teaching Child and Adolescent Mental Health Studies to Undergraduate College Students.

OBJECTIVE: The Child and Adolescent Mental Health Studies (CAMS) program is housed in a Liberal Arts undergraduate college of a large research university. Psychiatrists, clinical psychologists, and social workers at the university's medical center teach the courses. The purpose of this study is to evaluate the extent to which CAMS encourages graduates of the program to pursue a career in child and adolescent mental health (CAMH). METHODS: In 2015-2016, graduates of the CAMS program were invited to participate in a mixed methods study. In addition to statistical analyses, qualitative thematic analyses were performed to interpret free-text responses. RESULTS: Forty-five percent (314/702) of invited graduates completed the online survey. Interviews were conducted with 11% (34/314) of participants by study staff over the phone. Quantitative results suggested that 81% (149/185) of participants enrolled in educational programs after graduation due to an interest in CAMH. A significantly higher proportion of the total sample (t = 3.661, p < .001) reported that they changed their career goals while undergraduate students compared to those who did so after graduation. Results of qualitative interviews with 34 participants uncovered five key themes unique to CAMS that may explain the program's influence on graduates' career choices and career development: practitioners-as-instructors, instructor mentorship, novel course content, experiential learning opportunities, and career training and skills. CONCLUSIONS: Quantitative and qualitative results indicated that teaching college undergraduate students about CAMH encourages them to set career goals within the field. These findings suggest the utility of implementing similar programs at other undergraduate colleges.

Reoperation risk following the first operation for internal herniation in patients with laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the most commonly used surgical procedure in the treatment of morbid obesity in Denmark. Internal herniation (IH) and intermittent internal herniation (IIH) are probably the most common late complications in patients with LRYGB. The aim of this study was to investigate a possible increased risk of subsequent operations after an initial IH or IIH event. METHODS: This long-term follow-up study of patients who had surgery for an initial IH or IIH event in 2006-2011, based on the Danish National Patient Registry (NPR), was performed to 2013. During this period, mesenteric defects were not closed routinely during LRYGB. RESULTS: Data were retrieved from 12 221 patients with LRYGB from the NPR. A total of 383 patients had surgery for an initial IH or IIH event. Some 102 patients (26·6 (95 per cent c.i. 22·5 to 31·3) per cent) had a second operation. Twenty-seven (26·5 (18·9 to 35·8) per cent) of these 102 patients had a third operation, and five (19 (8 to 37) per cent) of the 27 had a fourth operation. Of the 383 patients diagnosed with an initial IH or IIH event, 72 (18·8 per cent) had a second IH/IIH event, 14 (3·7 per cent) had a third event, and three (0·8 per cent) a fourth event requiring surgery. CONCLUSION: Patients who have surgery for IH or IIH have a substantial risk of needing further operations.

CDX2 downregulation is associated with poor differentiation and MMR deficiency in colon cancer.

BACKGROUND: Homeobox genes are often deregulated in cancer and can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. CDX2 has been implicated in differentiation, proliferation, cell adhesion, and migration. In this study, we investigated CDX2 mRNA and protein expression in relation to the clinicopathological characteristics of colon cancer, including mismatch repair status and recurrence risk. METHODS: Tumor samples were obtained from colon cancer patients. Biopsies from tumor tissue and normal adjacent tissue were fixed in liquid nitrogen for RNA extraction or in formalin and paraffin embedded (FFPE) for immunohistochemical staining. CDX2 mRNA expression was evaluated by RT-qPCR. FFPE sections were stained for MLH1, MSH2, MSH6, PMS2, and CDX2. RESULTS: A total of 191 patient samples were included in the study and analyzed by immunohistochemistry. Of these samples, 97 were further evaluated by RT-qPCR. There was no significant difference in CDX2 mRNA expression between tumor and normal tissues. CDX2 mRNA expression was significantly lower in right-sided tumors (p<0.05), poorly differentiated tumors (p<0.05), and MMR-deficient tumors (p<0.05). Similarly, CDX2 protein expression was more often low or absent in right-sided tumors (p<0.01), poorly differentiated tumors (p<0.001), and MMR-deficient tumors (p<0.001). Low CDX2 protein or mRNA expression was not associated with recurrence risk. CONCLUSION: We found that CDX2 downregulation is associated with MMR deficiency, right-sided tumors, and poor differentiation at both the mRNA and protein level. Whether CDX2 plays an active role in tumor progression in MSI/MMR-deficient tumors remains to be elucidated.

Psychiatry's Next Generation: Teaching College Students About Mental Health.

OBJECTIVE: The authors describe an integrated area of study for undergraduate college students that targets an increase in knowledge of mental health issues in children, adolescents, and emerging adults; encourages mental health service utilization on college campuses; and exposes young minds to the possibilities of working with children and adolescents in the mental health field. METHODS: An overview of the program is provided, including the resources required to oversee and manage the program, student requirements, a description of the role that clinicians and researchers play as the program faculty, and an explanation of the tuition model. RESULTS: The program currently includes 40 courses with an annual enrollment of over 3000 students, resulting in departmental revenues that currently exceed $11 million per year. Student evaluations of the courses are very positive, and in a program survey students reported that their participation in the program had a positive impact on their life (84.2%) and impacted their career choice (60.2%). CONCLUSIONS: The benefits of the program include a valuable outreach to college students regarding the importance of seeking help for mental health issues, a positive influence on early career decision-making, opportunities for clinical and research educators to develop their scholarly areas of interest, and a significant source of departmental discretionary revenues.

Patient-reported genitourinary dysfunction after laparoscopic and open rectal cancer surgery in a randomized trial (COLOR II).

BACKGROUND: This article reports on patient-reported sexual dysfunction and micturition symptoms following a randomized trial of laparoscopic and open surgery for rectal cancer. METHODS: Patients in the COLOR II randomized trial, comparing laparoscopic and open surgery for rectal cancer, completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR38 questionnaire before surgery, and after 4 weeks, 6, 12 and 24 months. Adjusted mean differences on a 100-point scale were calculated using changes from baseline value at the various time points in the domains of sexual functioning, sexual enjoyment, male and female sexual problems, and micturition symptoms. RESULTS: Of 617 randomized patients, 385 completed this phase of the trial. Their mean age was 67·1 years. Surgery caused an anticipated reduction in genitourinary function after 4 weeks, with no significant differences between laparoscopic and open approaches. An improvement in sexual dysfunction was seen in the first year, but some male sexual problems persisted. Before operation 64·5 per cent of men in the laparoscopic group and 55·6 per cent in the open group reported some degree of erectile dysfunction. This increased to 81·1 and 80·5 per cent respectively 4 weeks after surgery, and 76·3 versus 75·5 per cent at 12 months, with no significant differences between groups. Micturition symptoms were less affected than sexual function and gradually improved to preoperative levels by 6 months. Adjusting for confounders, including radiotherapy, did not change these results. CONCLUSION: Sexual dysfunction is common in patients with rectal cancer, and treatment (including surgery) increases the proportion of patients affected. A laparoscopic approach does not change this. REGISTRATION NUMBER: NCT00297791 (http://www.clinicaltrials.gov).

Tumour stage and preoperative chemoradiotherapy influence the lymph node yield in stages I-III rectal cancer: results from a prospective nationwide cohort study.

AIM: The study aimed to determine whether the lymph node yield (LNY) in rectal cancer is influenced by patient-related and histopathological factors and the use of preoperative chemoradiotherapy (CRT). METHOD: An analysis was carried out of the LNY in a nationwide Danish cohort of 7950 patients, treated by curative resection of Stage I-III rectal cancer during the period 2001-2011. The impact of year of diagnosis, age, gender, pathological stage of the tumour (pT-stage) and preoperative CRT on LNY was analysed. RESULTS: Twenty-nine per cent of the patients received preoperative CRT. The median LNY was 13 [interquartile range (IQR): 8-19]. A total of 43.4% of the patients had an LNY of < 12. The median LNY increased from 8 (IQR: 5-12) to 20 (IQR: 13-28) LNs over the years of the study period (P < 0.0001). Gender and body mass index (BMI) had no impact on the median LNY. Age had a minor impact, with a range of 12 (IQR: 8-18) to 13 (IQR: 9-20) (P < 0.0001). The LNY ranged from 9 (IQR: 6-14) to 16 (IQR: 10-26), according to pT-stage (pT0-pT4) (P < 0.0001). Median LNY, according to preoperative CRT or no preoperative CRT, was 10 (IQR: 6-16) and 14 (IQR: 8-18), respectively (P < 0.0001). The percentages of patients with an LNY of < 12, according to preoperative CRT or no preoperative CRT, were 58.7% and 37.1%, respectively (P < 0.0001). CONCLUSION: An increase in the LNY over the period of the study was observed, probably reflecting improved quality of surgery and histopathology. A minor significant reduction of LNY was found with increasing age of the patient. LNY was significantly related to pT-stage and to the use of preoperative chemoradiotherapy. For these reasons the minimum harvest of 12 LNs as a surrogate marker for the oncological quality of surgery should be questioned.

Health-related quality of life after surgery for advanced and recurrent rectal cancer: a nationwide prospective study.

AIM: Advances in the treatment of rectal cancer have made it possible to perform complex rectal cancer surgery (COMP-RCS) in patients with primary advanced rectal cancer penetrating beyond the total mesorectal excision planes and in patients with locally recurrent rectal cancer. The aim of this study was to examine health-related quality of life (HRQoL) before and during the first 2 years after COMP-RCS. METHOD: Between 2001 and 2008, 180 patients were treated with COMP-RCS at Aarhus University Hospital. HRQoL was assessed preoperatively and 3, 6, 12, 18 and 24 months after surgery using three questionnaires. The results were compared with those for patients treated with standard rectal cancer surgery (STAN-RCS) and with data from the general Danish population (NORM-data). RESULTS: One hundred and twenty-two (68%) patients responded to the questionnaires. Of these 80 (66%) with disease-free survival for 2 years after surgery were included in the main analysis. The lowest level of functioning and the highest degree of symptoms were reported preoperatively. The majority of the HRQoL scales improved or remained stable during the first postoperative year; a decrease was observed for body image only. One year after surgery, HRQoL in patients treated with COMP-RSC was comparable to that for patients treated with STAN-RCS. Lower levels were found for physical and emotional role functioning, compared with NORM-data. CONCLUSION: Patients treated with COMP-RCS experienced improvement in HRQoL in the first year after surgery. One year after surgery, HRQoL was similar to that of patients treated with STAN-RCS. Compared with NORM-data, lower levels were found for physical and emotional role functioning.

Pediatric Insomnia.

Insomnia is the most common sleep disorder among all ages; unfortunately, however, child and adolescent insomnia is infrequently addressed. Given the importance of adequate sleep for proper brain development, pediatric populations are particularly vulnerable to the negative effects of insomnia. Therefore, proper clinical assessment and treatment of pediatric insomnia is crucial. This article is the result of a comprehensive literature review and serves as a guide to the disorder and how it presents differently across child development.