Down's Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship.

Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient's tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease.

Advancing workforce diversity by leveraging the Clinical and Translational Science Awards (CTSA) program.

Clinical trials continue to disproportionately underrepresent people of color. Increasing representation of diverse backgrounds among clinical research personnel has the potential to yield greater representation in clinical trials and more efficacious medical interventions by addressing medical mistrust. In 2019, North Carolina Central University (NCCU), a Historically Black College and University with a more than 80% underrepresented student population, established the Clinical Research Sciences Program with support from the Clinical and Translational Science Awards (CTSA) program at neighboring Duke University. This program was designed to increase exposure of students from diverse educational, racial, and ethnic backgrounds to the field of clinical research, with a special focus on health equity education. In the first year, the program graduated 11 students from the two-semester certificate program, eight of whom now hold positions as clinical research professionals. This article describes how leveraging the CTSA program helped NCCU build a framework for producing a highly trained, competent, and diverse workforce in clinical research responsive to the call for increased diversity in clinical trial participation.

Diversifying the Research Workforce as a Programmatic Priority for a Career Development Award Program at Duke University.

The National Institutes of Health (NIH) has prioritized efforts to increase diversity in the biomedical research workforce. NIH-funded institutional career development awards may serve as one mechanism to facilitate these efforts. In 2013, the Duke University KL2 program, an internal career development program funded by the National Center for Advancing Translational Sciences, set a goal to increase the number of investigators from underrepresented racial and ethnic groups (UREGs) to ≥ 50% of KL2 awardees. From 2013 to 2019, 133 KL2 applications were received, 38% from UREG investigators. Of the 21 scholars selected, 10 (47.6%) were UREG investigators; all were Black/African American. This represents a threefold increase in the proportion of UREG applications and a sixfold increase in the proportion of UREG KL2 scholars compared with Duke's previous KL2 cycles (2003-2012), during which only 13% of applicants and 8.3% of funded scholars were UREGs. Of the 12 KL2 scholars (7 UREG) who completed the program, 5 have received NIH funding as principal investigators of an external K award or R01, and 4 of them are UREG investigators; this constitutes a post-KL2 NIH funding success rate of 57% (4/7) for UREG scholars. Achieving this programmatic priority was facilitated by institutional support, clear communication of goals to increase the proportion of UREG KL2 awardees, and intentional strategies to identify and support applicants. Strategies included targeted outreach to UREG investigators, partnerships with other institutional entities, structured assistance for investigators with preparing their applications, and a KL2 program structure addressing common barriers to success for UREG investigators, such as lack of consistent mentorship, protected research time, and peer support. The authors' experience suggests that KL2 and other internal career development programs may represent a scalable, national strategy to increase diversity in the biomedical research workforce.

Supporting researchers through full-service hotline and consultation services: Success in simplicity, customization, and staffing.

Navigating the research domain at an academic medical center can be challenging, even for seasoned investigators. To address this, Duke University launched two initiatives: (1) a research navigation "hotline" to provide brief assistance with a variety of research questions; and (2) researcher onboarding and consultation, a one-to-one tailored offering to ensure that researchers are equipped to navigate research resources and processes effectively. The services are provided by the myRESEARCHnavigators (MRN) team, funded by Duke's CTSA. The diverse scientific backgrounds of the six team members align well with those of the research community, allowing for a good match between the researcher and MRN team member. The MRN team answers approximately 30 questions per month, and has provided consultations to almost 400 researchers. Both services receive high satisfaction ratings (4 or 5 stars [out of 5 stars] given to 90% of hotline answers, and 99% of researcher onboarding/consultation sessions). As of July 2019, the School of Medicine has determined that the consultations are critical to their mission and have made them a requirement for new research faculty. The team will continue marketing both services to encourage adoption.

Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders.

The link between movement abnormalities and psychotic disorders is presumed to reflect common neural mechanisms that influence both motor functions and vulnerability to psychosis. The prodromal period leading to psychotic disorders represents both a viable point for intervention and a developmental period that, if studied, could shed light on etiology; however, no published studies have examined the temporal progression of this link. A group with high levels of prodromal symptomatology (i.e., adolescents with schizotypal personality disorder [SPD]; n = 42) and both psychiatric controls (with other personality disorders or conduct disorder [OD]; n = 30) and nonpsychiatric controls ([NC]; n = 49) were recruited. Videotapes of structured psychiatric interviews were coded for movement abnormalities by raters blind to participants' diagnostic status, and follow-up assessments were conducted 1 year later. Controlling for psychotropic medications, the authors found that adolescents with SPD exhibited significantly more motor abnormalities in the face and upper body than did OD and NC controls. At baseline, movement abnormalities were positively correlated with the severity of positive, negative, and total prodromal symptoms. Within the SPD group, baseline movement abnormalities predicted symptom severity 1 year later. Movement abnormalities represent an early risk indicator that may be predictive of later symptom severity and potentially of psychosis onset.

Sex differences in digit ratio (2D:4D) are disrupted in adolescents with schizotypal personality disorder: altered prenatal gonadal hormone levels as a risk factor.

The 2nd to 4th finger digit ratio (2D:4D) is a sexually dimorphic feature determined during gestation indexing prenatal androgen/estrogen levels. More 'feminized' 2D:4D phenotype has been demonstrated in schizophrenia versus same-sex controls. This study examined 2D:4D in adolescents with schizotypal personality disorder (SPD). Among normal controls, right 2D:4D was significantly greater (more feminized) in females than males. We replicated laterality effects; significant sex differences only on right. There were no significant sex differences among SPDs. Diagnostic group differences were restricted to White/Caucasian males with greater right 2D:4D in SPDs. Findings suggest disruptions in prenatal gonadal hormones in vulnerability for schizophrenia.

Cognitive function and symptoms in adolescents with schizotypal personality disorder.

Cognitive deficits have been documented in schizophrenia and spectrum disorders. This study examines cognitive functioning and its relation to symptoms in adolescents with schizotypal personality disorder (SPD). Participants are 89 adolescents recruited for a study of youth at risk for Axis I disorders, especially psychosis. At intake, 34 met criteria for SPD, 38 for another Axis II disorder and/or conduct disorder (Other disorder-OD), and 17 did not currently meet criteria for any DSM-IV disorder (normal control-NC). At initial assessment, cognitive functioning was measured using subtests from the Wechsler Intelligence Scales and Wechsler Memory Scales (WMS), and symptoms were measured using the Structured Interview for Prodromal Symptoms (SIPS). At the time of this report, 50 were readministered the SIPS at 1-year follow-up (T2). The SPD group scored significantly below the NC group on the Arithmetic subtest of the Wechsler Intelligence Scales, but there was only limited evidence of group differences on the WMS. Poorer performance on the Wechsler Intelligence Scales was associated with greater severity of negative and disorganized symptoms. Deficits on the WMS were linked with more severe disorganized symptoms. The findings reported here are consistent with previous reports of limited cognitive deficits in adolescents with SPD, with the most marked deficits in mental arithmetic. The associations between symptoms and cognitive scores parallel those observed in adults with schizophrenia and spectrum disorder, and they are consistent with the notion that negative symptoms are more stable and partially reflect premorbid cognitive functions.

Gesture behavior in unmedicated schizotypal adolescents.

Schizotypal personality disorder is characterized by interpersonal and verbal communication deficits. Despite the important role of gesture in social communication, no published reports examine the use of gesture by individuals with SPD. In this study, raters code gesture from videotaped interviews of unmedicated adolescents with SPD, other personality disorders, or no Axis II disorder. Results indicate that SPD adolescents show significantly fewer gestures but do not differ from the other groups in overall rate of movement. The findings are discussed in light of brain regions involved in dysfunction, parallels to schizophrenia, and treatment implications.