A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma.

Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Chemicals specifically targeting senescent cells, so-called senolytics, constitute a promising avenue for improved cancer treatment in combination with targeted therapies. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCell-based integration of bulk and single-cell RNA-seq data identifies biological processes perturbed during senescence and predicts 90 new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.

A combinatorial approach to protect sensory tissue against cisplatin-induced ototoxicity.

Sensorineural Hearing Loss (SNHL) is a highly prevalent disorder involving permanent damage or loss to the inner ear's mechano-sensory hair cells and nerve fibers. Major contributing causes are ototoxic drugs, loud noises, and aging. Drug-induced hearing loss (DIHL), affects over 25% of patients treated with common therapeutics such as aminoglycoside antibiotics, loop diuretics or chemotherapeutics. A commonly used chemotherapeutic agent, cisplatin, is very effective for treating malignant tumors, but results in a majority of patients experiencing irreversible hearing loss and/or tinnitus. Additionally, since there is currently no FDA-approved treatments for SNHL, attenuation of ototoxicity is a major area of investigation in oncology, otolaryngology and hearing research. Several potential otoprotective agents have been investigated at the clinical trial stage, but none have progressed to a full FDA-approval. In this study, we investigated a combinatorial approach comprised of an antioxidant, a p53 inhibitor and a neurotrophin, as a multifactorial otoprotective treatment for cisplatin exposure. In vitro, HEI-OC1 cells, an immortalized organ of Corti epithelial cell line, pre-treated with this biotherapeutic cocktail had significantly reduced cisplatin-induced cell death, DNA fragmentation, and apoptotic activation. In an ex vivo study, rat pup D2-D3 organ of Corti explants, significant protection against cisplatin-based hair cell and neuronal loss was achieved by delivery of the same combinatorial pretreatment. Interestingly, the hair cell protection was localized to the basal and middle regions of the organ of Corti. Together, these findings highlight a novel approach to attenuate cisplatin ototoxicity and potentially prevent DIHL by addressing biological mechanisms of cisplatin ototoxicity.

Opioid prescribing for surgical dental procedures in dental clinics of military treatment facilities.

BACKGROUND: Variation in opioid prescribing rates among geographic regions is well known and, to the authors' knowledge, there have been no studies of variation from 1 dental clinic to another, and such variation might suggest an excess of opioid prescriptions. METHODS: The authors used a retrospective cohort design study of all dental encounter records for 819,453 soldiers in the dental clinics (n = 250) of the US Military Health System during the period from 2008 through 2017. RESULTS: There were 743,459 dental surgical encounters. Opioid prescriptions were filled for 36.7% of these encounters. Multinomial multilevel regression found statistically significant between-facility variance in opioid prescribing, which was partially explained via facility-level characteristics (region, type, and percentage of surgeries for young patients), and practice variables (mean percentage extractions, percentage periodontic surgery, and percentage specialists). CONCLUSIONS: The authors found a substantial variation in opioid prescribing among dental clinics in the US Military Health System. Dentists at 11 of the 30 largest military treatment facilities prescribed at a rate 4 percentage points higher than expected, and dentists at 9 of these military treatment facilities had a rate of 4 percentage points lower than expected. Additional study of the factors allowing the low-prescribing facilities to achieve these rates might lead to an overall decrease in opioid prescribing. PRACTICAL IMPLICATIONS: The authors' findings of dental opioid prescribing in the military can lead to appreciation of the guidelines from the American Dental Association and the American Association of Oral and Maxillofacial Surgeons, which suggest alternatives to opioid prescribing for surgical procedures, particularly for tooth extractions.

Development and Evaluation of a Cancer Literacy Intervention to Promote Mammography Screening Among Navajo Women: A Pilot Study.

PURPOSE: Develop and evaluate a mammography intervention that provides hope about cancer prevention and treatment. DESIGN: Pilot randomized controlled trial. SETTING: Two communities on the Navajo Nation. PARTICIPANTS: Navajo women and support persons. INTERVENTION: Both groups received standard care: one home visit discussing mammography pros/cons and barriers. The treatment group received an intervention based on Navajo language via an additional home visit with health education materials (written and oral) in English and Navajo, including a Navajo Cancer Glossary with a new descriptive phrase for cancer. ANALYSIS: Between control and intervention conditions, we compared baseline sociodemographics; changes from baseline to 3 months on mammography completion and breast cancer literacy scores. MEASURES: (1) intervention feasibility; (2) self- and clinic-reported mammography screening completion; (3) breast cancer literacy. RESULTS: A total of 25 participants were randomly assigned (13 treatment, 12 control), with 7 support persons in each arm. Mean age was 53 years, 90% had a high school degree or higher, 86% spoke Navajo and English. At 3 months, 44% had a clinically verified mammogram. Mammography completion was 57% among those with a support person and 27% among those without (P = .14). Intervention women reported more breast cancer beliefs consistent with mammography (P = .015). CONCLUSIONS: Increases in breast cancer beliefs consistent with mammography show promise. Findings highlight a need to tailor education materials to Navajo culture/language and focus on enhancing support.

A systematic review of team-building interventions in non-acute healthcare settings.

BACKGROUND: Healthcare is increasingly delivered in a team-based format emphasizing interdisciplinary coordination. While recent reviews have investigated team-building interventions primarily in acute healthcare settings (e.g. emergency or surgery departments), we aimed to systematically review the evidence base for team-building interventions in non-acute settings (e.g. primary care or rehabilitation clinics). METHODS: We conducted a systematic review in PubMed and Embase to identify team-building interventions, and conducted follow-up literature searches to identify articles describing empirical studies of those interventions. This process identified 14 team-building interventions for non-acute healthcare settings, and 25 manuscripts describing empirical studies of these interventions. We evaluated outcomes in four domains: trainee evaluations, teamwork attitudes/knowledge, team functioning, and patient impact. RESULTS: Trainee evaluations for team-building interventions were generally positive, but only one study associated team-building with statistically significant improvement in teamwork attitudes/knowledge. Similarly mixed results emerged for team functioning and patient impact. CONCLUSIONS: The evidence base for healthcare team-building interventions in non-acute healthcare settings is much less developed than the parallel literature for short-term team function in acute care settings. Only one intervention we identified has been tested in multiple non-acute settings by distinct research teams. Positive findings regarding the utility of team-building interventions are tempered by a lack of control conditions, inconsistency in outcome measures, and high probability of bias. Considering these results alongside the well-recognized costs of poor healthcare teamwork suggests that additional research is sorely needed to develop the evidence base for team-building in non-acute settings.

Adapting a Cancer Literacy Measure for Use Among Navajo Women.

PURPOSE: The authors designed a community-based participatory research study to develop and test a family-based behavioral intervention to improve cancer literacy and promote mammography among Navajo women. METHOD: Using data from focus groups and discussions with a community advisory committee, they adapted an existing questionnaire to assess cancer knowledge, barriers to mammography, and cancer beliefs for use among Navajo women. Questions measuring health literacy, numeracy, self-efficacy, cancer communication, and family support were also adapted. RESULTS: The resulting questionnaire was found to have good content validity, and to be culturally and linguistically appropriate for use among Navajo women. CONCLUSIONS: It is important to consider culture and not just language when adapting existing measures for use with AI/AN (American Indian/Alaskan Native) populations. English-language versions of existing literacy measures may not be culturally appropriate for AI/AN populations, which could lead to a lack of semantic, technical, idiomatic, and conceptual equivalence, resulting in misinterpretation of study outcomes.

Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia.

OBJECTIVE: To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. METHODS: Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher's exact test. RESULTS: Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%). CONCLUSIONS: Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials.

Development and pilot evaluation of Native CREST-a Cancer Research Experience and Student Training program for Navajo undergraduate students.

The Mayo Clinic Cancer Center and Diné College received funding for a 4-year collaborative P20 planning grant from the National Cancer Institute in 2006. The goal of the partnership was to increase Navajo undergraduates' interest in and commitment to biomedical coursework and careers, especially in cancer research. This paper describes the development, pilot testing, and evaluation of Native CREST (Cancer Research Experience and Student Training), a 10-week cancer research training program providing mentorship in a Mayo Clinic basic science or behavioral cancer research lab for Navajo undergraduate students. Seven Native American undergraduate students (five females, two males) were enrolled during the summers of 2008-2011. Students reported the program influenced their career goals and was valuable to their education and development. These efforts may increase the number of Native American career scientists developing and implementing cancer research, which will ultimately benefit the health of Native American people.

Design and rationale of a randomized controlled trial to reduce cardiovascular disease risk for patients with bipolar disorder.

BACKGROUND: Persons with bipolar disorder (BD) experience a disproportionate burden of medical comorbidity, notably cardiovascular disease (CVD), contributing to decreased function and premature mortality. We describe the design, rationale, and baseline findings for the Self-Management Addressing Heart Risk Trial (SMAHRT), a randomized controlled effectiveness trial of an intervention (Life Goals Collaborative Care; LGCC) designed to reduce CVD risk factors and improve physical and mental health outcomes in patients with BD. METHODS: Patients with BD and at least one CVD risk factor were recruited from a VA healthcare system and randomized to either LGCC or usual care (UC). LGCC participants attended four weekly, group-based self-management sessions followed by monthly individual contacts supportive of health behavior change and ongoing medical care management. In contrast, UC participants received monthly wellness newsletters. Physiological and questionnaire assessments measured changes in CVD outcomes and quality of life (QOL) over 24 months. RESULTS: Out of the 180 eligible patients, 134 patients were enrolled (74%) and 118 started the study protocols. At baseline (mean age=54, 17% female, 5% African American) participants had a high burden of clinical risk with nearly 70% reporting at least three CVD risk factors including, smoking (41%) and physical inactivity (57%). Mean mental and physical HRQOL scores were 1.5 SD below SF-12 population averages. CONCLUSION: SMAHRT participants experienced substantial CVD morbidity and risk factors, poor symptom control, and decreased QOL. LGCC is the first integrated intervention for BD designed to mitigate suboptimal health outcomes by combining behavioral medicine and care management strategies.

Quality of general medical care among patients with serious mental illness: does colocation of services matter?

OBJECTIVE: This study was conducted to determine whether patients with serious mental illness receiving care in Veterans Affairs (VA) mental health programs with colocated general medical clinics were more likely to receive adequate medical care than patients in programs without colocated clinics based on a nationally representative sample. METHODS: The study included all VA patients with diagnoses of serious mental illness in fiscal year (FY) 2006-2007 who were also part of the VA's External Peer Review Program (EPRP) FY 2007 random sample and who received care from VA facilities (N=107 facilities) with organizational data from the VA Mental Health Program Survey (N=7,514). EPRP included patient-level chart review quality indicators for common processes of care (foot and retinal examinations for diabetes complications; screens for colorectal health, breast cancer, and alcohol misuse; and tobacco counseling) and outcomes (hypertension, diabetes blood sugar, and lipid control). RESULTS: Ten out of 107 (10%) mental health programs had colocated medical clinics. After adjustment for organizational and patient-level factors, analyses showed that patients from colocated clinics compared with those without colocation were more likely to receive foot exams (OR=1.87, p<.05), colorectal cancer screenings (OR=1.54, p<.01), and alcohol misuse screenings (OR=2.92, p<.01). They were also more likely to have good blood pressure control (<140/90 mmHg; OR=1.32, p<.05) but less likely to have glycosylated hemoglobin <9% (OR=.69, p<.05). CONCLUSIONS: Colocation of medical care was associated with better quality of care for four of nine indicators. Additional strategies, particularly those focused on improving diabetes control and other chronic medical outcomes, might be warranted for patients with serious mental illness.

Development and pilot evaluation of a cancer-focused summer research education program for [corrected] Navajo undergraduate students.

This paper describes the development and pilot testing of a 10-week cancer research education program for Navajo undergraduate students. The program was piloted at Diné College with 22 undergraduates (7 men, 15 women) in 2007 and 2008. Students completed a pre-post program survey assessing attitudes, opinions, and knowledge about research and about cancer. The program was found to be culturally acceptable and resulted in statistically significant changes in some of the attitudes and opinions about research and cancer. Combining all 13 knowledge items, there was a significant (p = 0.002) change in the mean total correct percent from baseline [70.3 (SD = 15.9)] to post-program [82.1 (SD = 13.1)]. The curriculum was adapted for a new cancer prevention and control course now offered at Diné College, enhancing sustainability. Ultimately, these efforts may serve to build capacity in communities by developing a cadre of future Native American scientists to develop and implement cancer research.

Qualitative investigation of factors contributing to effective nutrition education for Navajo families.

OBJECTIVES: Obesity rates in American Indian and Alaskan Native children are a major health threat, yet effective ways to address this remain elusive. Building on an earlier dietary assessment of Navajo Head Start families which indicated a gap in parental nutrition awareness despite a strong program emphasis, the aim of this project was to identify culturally relevant nutrition education strategies for Navajo parents and educators of young children. METHODS: Eight focus group interviews were conducted with 41 parents and early childhood education paraprofessionals to identify contributors to both healthful and unhealthy food ways of Navajo preschoolers. RESULTS: were presented in two community venues to verify the themes and discuss implications. Results Barriers to healthful eating included availability/cost, parenting/control, preferences/habits, time pressures, and knowledge/education. Enablers to healthful eating included the categories of schools/education, and support/modeling. Reactions to these findings during community forums suggested (1) the need for stronger parenting and parental control over the food environment; (2) community-level action to address these barriers; and (3) the need for knowledge and culturally relevant educational strategies for caregivers and children. CONCLUSIONS: Implications for interventions include building upon existing community resources to enhance culturally relevant and respectful parental, family, and community support for affordable and acceptable food experiences and choices for young children and their families.

Familial risk and colorectal cancer screening health beliefs and attitudes in an insured population.

OBJECTIVE: To examine the relationship between health beliefs and attitudes toward colorectal cancer screening, strength of family history risk, and being appropriately screened for colorectal cancer. METHODS: In February 2004, 7000 randomly selected members of a multi-specialty group practice located in Boston, MA were mailed a brief survey that was used to ascertain colorectal cancer family history. A follow-up survey that contained questions representing selected constructs of the Health Belief Model, Theory of Planned Behavior, and healthcare experiences was then mailed to all 355 individuals who reported a family history in the initial survey and 710 randomly selected participants with no colorectal cancer family history. RESULTS: Participants who were appropriately screened had higher mean scores for perceived cancer risk, subjective norms, and perceived benefits and lower scores for perceived barriers. Multivariate findings indicate that having high perceptions of risk for colorectal cancer was a significant correlate of being screened appropriately among individuals with a strong family history. CONCLUSIONS: For those at greatest colorectal cancer risk due to family history, ensuring that these individuals understand their personal risk might lead to increased colorectal cancer screening participation. Future intervention research is warranted to examine if raising perceptions of risk can increase screening behaviors in individuals with colorectal cancer risk due to family history.

Screening patients with a family history of colorectal cancer.

OBJECTIVES: To compare screening practices and beliefs in patients with and without a clinically important family history. DESIGN: We mailed a brief questionnaire asking about family history and a second, longer survey asking about knowledge of and beliefs about colorectal cancer to all respondents with a family history and a random sample of respondents without a family history of colorectal cancer. We reviewed electronic medical records for screening examinations and recording of family history. PARTICIPANTS: One thousand eight hundred seventy of 6,807 randomly selected patients ages 35-55 years who had been continuously enrolled in a large multispecialty group practice for at least 5 years. MEASUREMENTS: Recognition of increased risk, screening practices, and beliefs-all according to strength of family history and patient's age. RESULTS: Nineteen percent of respondents reported a family history of colorectal cancer. In 11%, this history was strong enough to warrant screening before age 50 years. However, only 39% (95% CI 36, 42) of respondents under the age of 50 years said they had been asked about family history and only 45% of those with a strong family history of colorectal cancer had been screened appropriately. Forty-six percent of patients with a strong family history did not know that they should be screened at a younger age than average risk people. Medical records mentioned family history of colorectal cancer in 59% of patients reporting a family history. CONCLUSIONS: More efforts are needed to translate information about family history of colorectal cancer into the care of patients.