Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains.

Despite unequivocal roles in disease, transcription factors (TFs) remain largely untapped as pharmacologic targets due to the challenges in targeting protein-protein and protein-DNA interactions. Here we report a chemical strategy to generate modular synthetic transcriptional repressors (STRs) derived from the bHLH domain of MAX. Our synthetic approach yields chemically stabilized tertiary domain mimetics that cooperatively bind the MYC/MAX consensus E-box motif with nanomolar affinity, exhibit specificity that is equivalent to or beyond that of full-length TFs and directly compete with MYC/MAX protein for DNA binding. A lead STR directly inhibits MYC binding in cells, downregulates MYC-dependent expression programs at the proteome level and inhibits MYC-dependent cell proliferation. Co-crystallization and structure determination of a STR:E-box DNA complex confirms retention of DNA recognition in a near identical manner as full-length bHLH TFs. We additionally demonstrate structure-blind design of STRs derived from alternative bHLH-TFs, confirming that STRs can be used to develop highly specific mimetics of TFs targeting other gene regulatory elements.

Parental vaccine hesitancy and concerns regarding the COVID-19 virus.

PURPOSE: This study assessed parental vaccine hesitancy in a metropolitan area of the United States. The study aimed to determine what characteristics and contributing factors influenced parental vaccine hesitancy and concerns regarding COVID-19. DESIGN AND METHODS: An online survey was used to recruit 93 parents to answer demographic and vaccine hesitancy information. Vaccine hesitancy was measured using the Parent Attitudes about Childhood Vaccines survey. The study was conducted between June 2020 and September 2020 during the COVID-19 pandemic. RESULTS: The rate of vaccine hesitancy was 15%. One hundred percent of vaccine hesitant parents were mothers, at least 30 years of age, married, and had completed at least some college. When characteristics of vaccine hesitant parents were compared to non-hesitant parents, the hesitant parents reported having more children, with 93% reporting two or more children compared to only 74% of non-hesitant parents (p = 0.046). Fifty percent of hesitant parents reported no concerns regarding COVID-19 compared to only 20% of non-hesitant parents (p = 0.006), and significantly less hesitant parents reported willingness to have their children receive a safe, effective COVID-19 vaccine if it were available compared to non-hesitant parents (p < 0.001). CONCLUSIONS: Our findings indicate that older mothers with two or more children are more likely to be vaccine hesitant and this hesitancy extends to the current COVID-19 pandemic. PRACTICE IMPLICATIONS: Healthcare providers can use the results of this study to identify parents at risk for vaccine hesitancy and initiate individualized education to promote on-time childhood vaccination.

Tracking physical activity in baccalaureate nursing students in the United States prior to graduation: A longitudinal study.

OBJECTIVE: To evaluate changes in physical activity among baccalaureate nursing students over time. DESIGN: Longitudinal descriptive study. SETTING: Baccalaureate nursing program at a four-year university in the United States. PARTICIPANTS: Fifty-two male (n = 4) and female (n = 48) nursing students. METHODS: At the beginning and end (weeks 1-2 and 15-16) of the three semesters prior to graduation, students completed the International Physical Activity Questionnaire (IPAQ) and their body mass index (BMI) was calculated. Based on the IPAQ, physical activity was calculated as MET-minutes per week of vigorous, moderate, and walking activities, using metabolic equivalents of 8.0 METS for vigorous, 4.0 METS for moderate, and 3.3 METS for walking. RESULTS: At baseline, students were 21.3 ±â€¯1.4 years old with a BMI of 23.5 ±â€¯2.9 kg/m2. BMI increased throughout the study and prior to graduation was 23.9 ±â€¯3.2 kg/m2 (p = 0.039). Overall, students maintained high physical activity levels that did not change statistically. Walking was the predominant activity, followed by vigorous and then moderate activity. Walking and vigorous activity displayed opposing patterns. Vigorous activity decreased over the first three measurement periods (p = 0.029), increased for the fourth period, and then decreased again over the last two periods (p = 0.037 compared to baseline). By comparison, walking increased over the first three measurements (p = 0.002) and then decreased again (p = 0.015). When students were grouped by physical activity level (moderate vs. high), there were significant between-group differences in vigorous activity and walking. At baseline and end of study, the moderate activity group participated in 58% and 49% less vigorous activity, and 83% and 45% less walking than the high activity group. CONCLUSION: In this group of baccalaureate nursing students, overall physical activity did not decline with time. Students participated in sufficient physical activity to promote health, and after graduation, they are likely to provide effective patient counselling regarding healthy lifestyles.

Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: The long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established. METHODS: Patients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR. RESULTS: Seventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I. CONCLUSIONS: A combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL.