Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer.

Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Predictors of Missed Follow-up Visits in the National Traumatic Brain Injury Model Systems Cohort Study.

OBJECTIVE: To identify key variables that could predict risk of loss to follow-up (LTFU) in a nationally funded longitudinal database of persons with traumatic brain injury. DESIGN: Secondary analysis of a prospective longitudinal cohort study. SETTING: Traumatic Brain Injury Model System (TBIMS) Centers in the US. PARTICIPANTS: A total of 17,956 TBIMS participants (N=17,956) with interview status data available were included if eligible for 1-, 2-, 5-, 10-, 15-, or 20-year follow-ups between October 31, 1989, and September 30, 2020. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Follow-up data collection completion status at years 1, 2, 5, 10, 15, and 20. RESULTS: Information relevant to participants' history, injury characteristics, rehabilitation stay, and patterns of follow-up across 20 years were considered using a series of logistic regression models. Overall, LTFU rates were low (consistently <20%). The most robust predictors of LTFU across models were missed earlier follow-ups and demographic factors including Hispanic ethnicity, lower education, and lack of private health insurance. CONCLUSIONS: Efforts to retain participants in such social disadvantaged or minority groups are encouraged given their disproportionate rate of LTFU. Repeated attempts to reach participants after a previously missed assessment are beneficial because many participants that missed 1 or more follow-ups were later recovered.

Analysis of Airway Management for Cesarean Delivery: Use of Risk and Proportion Differences.

OBJECTIVES: Securing the parturient airway is essential during general anesthesia for cesarean delivery. The purpose of this study was to compare inferior airway views provided by the use of three commonly available laryngoscopy blades-Macintosh, Miller, or Glidescope Mac-Style-to the incidence of difficult orotracheal intubation. METHODS: Following institutional review board approval, data from 449 electronic medical records in parturients undergoing general anesthesia for cesarean delivery were extracted during a 6-year period. The association of these blades with difficult orotracheal intubation was analyzed with risk and proportion differences measures of effect size. RESULTS: The overall incidence of difficult orotracheal intubation was 4.2% (95% confidence interval 2.7 - 6.5%), with 6 failed orotracheal intubations (5 laryngeal mask airways rescues and 1 mask rescue). Clinically important increases in risk differences for difficult orotracheal intubation were observed in parturients with restricted mouth openings, modified Mallampati III and IV views, and reduced thyromental distances. When modified Cormack-Lehane views were grouped into III and IV versus I and II cohorts; proportion differences for difficult orotracheal intubation were dependent upon the type of blade used, with the Miller blade providing the lowest proportion difference. CONCLUSIONS: Miller blade laryngoscopy provided the lowest proportion difference for difficult orotracheal intubation during general anesthesia for cesarean delivery. Miller blade laryngoscopy provides effective procurement of the parturient airway.

Relationships of self-awareness and facial affect recognition to social communication ability in persons with traumatic brain injury.

Traumatic brain injury (TBI) can cause changes to the injured person's physical ability, cognitive functioning, and social interactions. Since these attributes largely determine a person's concept of who they are, TBI poses a threat to sense of self. Due to the importance of social communication skills for community integration, impairment of these skills is a particular threat to sense of self. The present investigation sought to explore characteristics that influence social communication abilities. We hypothesized that both ability to interpret facial affect and self-awareness would be associated with communication ability. We also expected that facial affect recognition would influence self-awareness and that the effect of facial affect recognition on social communication would be partially mediated by self-awareness. For this prospective cohort study, participants were 77 individuals with documented TBI. Of these, 65% were male and 83% sustained severe injuries. The hypothesized association of facial affect recognition with social communication was demonstrated with path analysis as was the effect of facial affect recognition on self-awareness. However, the effect of facial affect recognition on social communication was not mediated by self-awareness. In addition, social communication was associated with employment, social integration, and loneliness. Findings highlighted the importance of social communication after TBI.

Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage.

BRCA1 is a breast and ovarian tumor suppressor. Given its numerous incompletely understood functions and the possibility that more exist, we performed complementary systematic screens in search of new BRCA1 protein-interacting partners. New BRCA1 functions and/or a better understanding of existing ones were sought. Among the new interacting proteins identified, genetic interactions were detected between BRCA1 and four of the interactors: TONSL, SETX, TCEANC, and TCEA2. Genetic interactions were also detected between BRCA1 and certain interactors of TONSL, including both members of the FACT complex. From these results, a new BRCA1 function in the response to transcription-associated DNA damage was detected. Specifically, new roles for BRCA1 in the restart of transcription after UV damage and in preventing or repairing damage caused by stabilized R loops were identified. These roles are likely carried out together with some of the newly identified interactors. This new function may be important in BRCA1 tumor suppression, since the expression of several interactors, including some of the above-noted transcription proteins, is repeatedly aberrant in both breast and ovarian cancers.

A randomized controlled trial of acceptance and commitment therapy for psychological distress among persons with traumatic brain injury.

Psychological distress is common in persons with traumatic brain injury (TBI) but treatments remain underdeveloped. This randomized controlled trial of Acceptance and Commitment Therapy (ACT) was designed to address this gap. Ninety-three persons with medically-documented complicated mild to severe TBI, normal-to-mildly impaired memory, and clinically significant psychological distress in the chronic phase of recovery were randomized to receive eight weeks of ACT (manualized with adaptations to address TBI-related cognitive impairments) or a single session of needs assessment, brief counseling/education, and referral. The ACT group showed significantly greater reduction of psychological distress (Brief Symptom Inventory 18) and demonstrated improvements in psychological flexibility and commitment to action (Acceptance and Action Questionnaire-II (AAQ-II) scores). The number of treatment responders (post-treatment BSI 18 GSI T scores <63) was larger in the ACT group than in the control group. Entry of AAQ-II scores into the model of between-group differences in BSI 18 GSI T scores indicated that core ACT processes explained the variance in treatment group outcomes. Provision of ACT reduces psychological distress in persons with TBI in the chronic phase of recovery when adaptations are made to accommodate TBI-related cognitive impairments. Additional clinical trials with a structurally equivalent control group are needed.

Inter-breed diversity and temporal dynamics of the faecal microbiota in healthy horses.

Understanding gut microbiota similarities and differences across breeds in horses has the potential to advance approaches aimed at personalized microbial modifications, particularly those involved in improving sport athletic performance. Here, we explore whether faecal microbiota composition based on faecal 16S ribosomal RNA gene sequencing varies across six different sport breeds at two time points 8 months apart within a cohort of 189 healthy horses cared for under similar conditions. Lusitano horses presented the smallest and Hanoverians the greatest bacterial diversity. We found subtle but significant differences in ß-diversity between Lusitano, Anglo Arabian and the central European breeds, and we reproduced these results across the two time points. Repeat sampling of subjects showed community to be temporally more stable in Lusitano and Anglo Arabian breeds. Additionally, we found that 27 genera significantly varied in abundance across breeds. Overall, 33% of these taxa overlapped with previously identified taxa that were associated with genetic variation in humans or other species. However, a non-significant correlation was observed between microbial composition and the host pedigree-based kinship. Despite a notable variation in the diversity and composition of the faecal microbiota, breed exerted limited effects on the equine faecal microbiota.

Understanding the response to endurance exercise using a systems biology approach: combining blood metabolomics, transcriptomics and miRNomics in horses.

BACKGROUND: Endurance exercise in horses requires adaptive processes involving physiological, biochemical, and cognitive-behavioral responses in an attempt to regain homeostasis. We hypothesized that the identification of the relationships between blood metabolome, transcriptome, and miRNome during endurance exercise in horses could provide significant insights into the molecular response to endurance exercise. For this reason, the serum metabolome and whole-blood transcriptome and miRNome data were obtained from ten horses before and after a 160 km endurance competition. RESULTS: We obtained a global regulatory network based on 11 unique metabolites, 263 metabolic genes and 5 miRNAs whose expression was significantly altered at T1 (post- endurance competition) relative to T0 (baseline, pre-endurance competition). This network provided new insights into the cross talk between the distinct molecular pathways (e.g. energy and oxygen sensing, oxidative stress, and inflammation) that were not detectable when analyzing single metabolites or transcripts alone. Single metabolites and transcripts were carrying out multiple roles and thus sharing several biochemical pathways. Using a regulatory impact factor metric analysis, this regulatory network was further confirmed at the transcription factor and miRNA levels. In an extended cohort of 31 independent animals, multiple factor analysis confirmed the strong associations between lactate, methylene derivatives, miR-21-5p, miR-16-5p, let-7 family and genes that coded proteins involved in metabolic reactions primarily related to energy, ubiquitin proteasome and lipopolysaccharide immune responses after the endurance competition. Multiple factor analysis also identified potential biomarkers at T0 for an increased likelihood for failure to finish an endurance competition. CONCLUSIONS: To the best of our knowledge, the present study is the first to provide a comprehensive and integrated overview of the metabolome, transcriptome, and miRNome co-regulatory networks that may have a key role in regulating the metabolic and immune response to endurance exercise in horses.

Role of resilience in the rehabilitation of adults with acquired brain injury.

PURPOSE: The goals of this review paper are to present an overview of the literature on resilience in adults with ABI, to describe approaches to measuring resilience in clinical practice and to discuss practical suggestions for promoting resilience in rehabilitation of adults with ABI. METHOD: We employed systematic review of journal articles, books, and websites related to resilience in adults with acquired brain injury (ABI). RESULTS: Resilience was associated with adaptation and adjustment for individuals faced with serious injury such as ABI. However, research examining the construct of resilience is limited. CONCLUSION: While rehabilitation typically focuses on the identification and reduction of impairments for improving functioning, a focus on resilience may allow for recovery in a broader sense that exceeds expected outcomes.

Sex-Based Differences in Perceived Pragmatic Communication Ability of Adults With Traumatic Brain Injury.

OBJECTIVE: To identify sex-based differences in self-reported and close other-reported perceptions of communication behaviors in adults with traumatic brain injury (TBI). DESIGN: Between-groups comparison of questionnaire data from men and women with TBI and their close others. SETTING: University academic department. PARTICIPANTS: Adults with medically documented TBI (n=160) and adults without TBI (n=81; control group) (N=241). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: La Trobe Communication Questionnaire, a standardized measure of communication problems in everyday life. RESULTS: Participants with TBI endorsed more communication problems than controls (P<.001). There were no significant differences in self-ratings (P=.20) or in the ratings of close others (P=.09) in communication behaviors of men with TBI compared with women with TBI. There was no difference between the self-ratings of women with TBI and their close others (P=.59). However, men with TBI significantly underreported communication problems compared with reports of close others (P<.001). CONCLUSIONS: Women with TBI might be more accurate than men with TBI in recognizing their own pragmatic communication problems.

HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability.

Here, we show that the human homologue of the Caenorhabditis elegans biological clock protein CLK-2 (HCLK2) associates with the S-phase checkpoint components ATR, ATRIP, claspin and Chk1. Consistent with a critical role in the S-phase checkpoint, HCLK2-depleted cells accumulate spontaneous DNA damage in S-phase, exhibit radio-resistant DNA synthesis, are impaired for damage-induced monoubiquitination of FANCD2 and fail to recruit FANCD2 and Rad51 (critical components of the Fanconi anaemia and homologous recombination pathways, respectively) to sites of replication stress. Although Thr 68 phosphorylation of the checkpoint effector kinase Chk2 remains intact in the absence of HCLK2, claspin phosphorylation and degradation of the checkpoint phosphatase Cdc25A are compromised following replication stress as a result of accelerated Chk1 degradation. ATR phosphorylation is known to both activate Chk1 and target it for proteolytic degradation, and depleting ATR or mutation of Chk1 at Ser 345 restored Chk1 protein levels in HCLK2-depleted cells. We conclude that HCLK2 promotes activation of the S-phase checkpoint and downstream repair responses by preventing unscheduled Chk1 degradation by the proteasome.

Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins.

Post-translational modification (PTM) of proteins plays an important part in mediating protein interactions and/or the recruitment of specific protein targets. PTM can be mediated by the addition of functional groups (for example, acetylation or phosphorylation), peptides (for example, ubiquitylation or sumoylation), or nucleotides (for example, poly(ADP-ribosyl)ation). Poly(ADP-ribosyl)ation often involves the addition of long chains of ADP-ribose units, linked by glycosidic ribose-ribose bonds, and is critical for a wide range of processes, including DNA repair, regulation of chromosome structure, transcriptional regulation, mitosis and apoptosis. Here we identify a novel poly(ADP-ribose)-binding zinc finger (PBZ) motif in a number of eukaryotic proteins involved in the DNA damage response and checkpoint regulation. The PBZ motif is also required for post-translational poly(ADP-ribosyl)ation. We demonstrate interaction of poly(ADP-ribose) with this motif in two representative human proteins, APLF (aprataxin PNK-like factor) and CHFR (checkpoint protein with FHA and RING domains), and show that the actions of CHFR in the antephase checkpoint are abrogated by mutations in PBZ or by inhibition of poly(ADP-ribose) synthesis.

Prognostic importance of self-reported traits/problems/strengths and environmental barriers/facilitators for predicting participation outcomes in persons with traumatic brain injury: a systematic review.

OBJECTIVE: To conduct a systematic review of the prognostic value of self-reported traits/problems/strengths and environmental barriers/facilitators for participation outcomes in persons with traumatic brain injury (TBI). DATA SOURCES: Articles published through August 15, 2013, obtained by conducting electronic searches of PubMed, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature databases and a review of reference lists of reviewed articles. STUDY SELECTION: Reviewed articles were written in English and presented findings on adult humans with TBI, participation outcomes, and ≥ 1 self-reported trait/problem/strength (eg, depression, pain, coping style) and/or ≥ 1 environment barrier/facilitator (eg, social support, family functioning, access to services). DATA EXTRACTION: Each of the 996 abstracts was examined by 2 reviewers, and those failing to meet all inclusion criteria were excluded. Data were extracted from the 63 retained articles by 2 independent reviewers, who met to resolve any differences in study quality rating or evidence recorded. Study quality was determined using American Academy of Neurology (AAN) criteria. DATA SYNTHESIS: Conclusions regarding prognostic importance of self-report and environmental barrier/facilitator variables were made using AAN criteria. Conclusions regarding barrier/facilitator variables indicated that access to transportation, access to services, and participation in social interaction were possibly predictive of employment outcome, whereas living arrangements and social support were possibly not predictive of employment outcome. Conclusions regarding self-report variables indicated that the number of postconcussive symptoms, fatigue, and physical competence were probably predictive of employment and need for supervision, whereas self-efficacy was probably not predictive of employment. Subjective well-being, pain, and social interaction were possibly predictive of employment, whereas coping style was possibly not predictive. CONCLUSIONS: Although additional investigation is needed, self-report variables are likely to make important contributions to predicting participation outcomes. Future research should be guided by coherent conceptual models and use a consistent set of assessment instruments to facilitate comparisons between studies.

Preinjury coping, emotional functioning, and quality of life following uncomplicated and complicated mild traumatic brain injury.

OBJECTIVE: To identify preinjury coping profiles among adults with uncomplicated mild traumatic brain injury (mTBI) and complicated mTBI and to determine whether preinjury coping profiles contribute to the prediction of emotional functioning and quality of life (QOL) 3 months post-mTBI. PARTICIPANTS: One hundred eighty-seven persons with medically documented mTBI (uncomplicated mTBI, n = 89; complicated mTBI, n = 98) were recruited from the emergency center of a level I trauma center and followed in community 3 months post-mTBI. MEASURES: The Ways of Coping Questionnaire was administered within 2 weeks of injury. Cluster analysis was used to group participants on basis of their preinjury use of problem-focused and avoidant coping strategies. The Brief Symptom Inventory and the 36-item Short-Form Health Survey were administered 3 months postinjury. RESULTS: Cluster analysis distinguished 3 distinct preinjury coping profiles that were differentially associated with outcomes. Participants who used avoidant coping showed the worse emotional functioning and QOL outcomes, although this cluster also reported high usage of problem-focused strategies. Preinjury coping profiles explained a significant proportion of the variance in depression, anxiety, and mental health QOL at 3 months postinjury beyond that accounted for by demographic characteristics and mTBI severity. CONCLUSIONS: Cluster analysis holds practical value in illustrating the pattern of coping strategies used by person with uncomplicated and complicated mTBI. It appears worthwhile to address coping in future trials of interventions that are aimed at improving emotional functioning after mTBI.

Improving secondary stroke self-care among underserved ethnic minority individuals: a randomized clinical trial of a pilot intervention.

The overall purpose of this study was to pilot a multibehavioral, brief, stroke self-care treatment adapted for implementation with underserved racial/ethnic minority groups and to test the moderating effects of anxiety and depression on engagement in secondary stroke-prevention behaviors. Fifty-two participants were randomized to the secondary stroke prevention (STOP) (N = 27) or usual care (N = 25) group. The STOP program consisted of 3 culturally tailored information sessions and goal-setting activities that were delivered in person by a research assistant. Participants were assessed at baseline and 4-week follow-up for stroke knowledge, exercise, fruit and vegetable consumption, tobacco and alcohol use, and medication adherence (primary outcomes) and anxiety and depression (moderator variables). Between-groups analysis of covariance and logistic multiple regressions revealed significant between-group differences for stroke knowledge, tobacco use and moderating effects between tobacco and anxiety, and improved alcohol use. The STOP program decreased secondary stroke risk factors among underserved racial/ethnic minorities and should be tested in large-scale trials.

Functional and physical interaction between the mismatch repair and FA-BRCA pathways.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and an increased risk for leukemia and cancer. Fifteen proteins thought to function in the repair of DNA interstrand crosslinks (ICLs) comprise what is known as the FA-BRCA pathway. Activation of this pathway leads to the monoubiquitylation and chromatin localization of FANCD2 and FANCI. It has previously been shown that FANCJ interacts with the mismatch repair (MMR) complex MutLα. Here we show that FANCD2 interacts with the MMR proteins MSH2 and MLH1. FANCD2 monoubiquitylation, foci formation and chromatin loading are greatly diminished in MSH2-deficient cells. Human or mouse cells lacking MSH2 or MLH1 display increased sensitivity and radial formation in response to treatment with DNA crosslinking agents. Studies in human cell lines and Drosophila mutants suggest an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair. Surprisingly, the interaction between MSH2 and MLH1 is compromised in multiple FA cell lines, and FA cell lines exhibit deficient MMR. These results suggest a significant role for MMR proteins in the activation of the FA pathway and repair of ICLs. In addition, we provide the first evidence for a defect in MMR in FA cell lines.

Cesarean delivery in the hybrid operating suite: a promising new location for high-risk obstetric procedures.

BACKGROUND: The increasing cesarean delivery rate and attendant placental implantation abnormalities, coupled with increasing general medical complexity in the obstetric population, has driven innovation to optimize the care of high-risk parturients during delivery. Novel and multidisciplinary approaches and locations may enhance the options available for care. METHODS: We reviewed the records of all 11 patients who underwent cesarean delivery in our hybrid operating suite between December 2007 and March 2013 and describe the high-risk cesarean deliveries. RESULTS: The most common indication for the use of the hybrid operating suite was an increased risk of hemorrhage, most commonly due to abnormal placental implantation. Other indications included cardiovascular disease and intracranial pathology. CONCLUSION: The hybrid operating suite may be an alternative location for obstetric delivery, and our experience suggests that this environment may prove advantageous for patients with a variety of comorbid conditions.

The gut mucin-microbiota interactions: a missing key to optimizing endurance performance.

Endurance athletes offer unique physiology and metabolism compared to sedentary individuals. Athletes training at high intensities for prolonged periods are at risk for gastrointestinal disturbances. An important factor in endurance performance is the integrity and function of the gut barrier, which primarily depends on heavily O-glycosylated mucins. Emerging evidence shows a complex bidirectional dialogue between glycans on mucins and gut microorganisms. This review emphasizes the importance of the crosstalk between the gut microbiome and host mucus mucins and some of the mechanisms underlying this symbiosis. The contribution of mucin glycans to the composition and functionality of the gut microbiome is discussed, as well as the persuasive impact of the gut microbiome on mucin composition, thickness, and immune and metabolic functions. Lastly, we propose natural and synthetic glycans supplements to improve intestinal mucus production and barrier function, offering new opportunities to enhance endurance athletes' performance and gut health.

Point-of-care Ultrasound Identification of Tension Hydrothorax in the Emergency Department: A Case Series.

INTRODUCTION: Tension hydrothorax is an uncommon emergent condition in which hemodynamic instability and respiratory compromise may occur. Emergency physicians may diagnose tension hydrothorax by point-of-care ultrasound. CASE SERIES: We discuss the key sonographic features assisting in identification. Four patients with history of malignancy who were found to have tension hydrothorax exhibited the following common ultrasound findings: massive, left-sided pleural effusion; complete, compressive atelectasis; and shift of cardiac structures into the right hemithorax, resulting in right-sided probe placement to obtain cardiac views. CONCLUSION: This is the first instance to our knowledge of point-of-care ultrasound findings in tension hydrothorax to be described in the literature.

Students' Perceptions of Their Student-Operated Restaurant Experience: A Qualitative Study.

As there is a rapid increase in the consumption of food outside the home, it is essential that future foodservice managers are well prepared for their critical role in menu creation and nutrition care planning in a variety of foodservice establishments. Student-operated restaurants (SORs) are one method of experiential learning used to educate future foodservice managers. This study aimed to explore the students' perceptions of their SOR experience and the extent to which nutrition concepts were incorporated in their program. This is a research area that has not been explored previously. For this study, a total of eighteen students from four universities were recruited via email to participate in interviews. Results from the qualitative thematic analysis of interview data revealed the following three overarching themes related to students' SOR experience: (1) Interpersonal Relationships and Mentoring, (2) Assessment of Immediate Experience, and (3) Moving Forward, Added Value, and Growth. Regarding nutrition, while some students felt that nutrition principles were effectively addressed during their SOR experience, other students acknowledged a lack of nutritional emphasis in their SOR and expressed a desire for a greater application of the nutritional principles learned in other classes. The SOR experience described by students was rich as they developed a variety of relationships and skills.