Conservation Weighting Functions Enable Covariance Analyses to Detect Functionally Important Amino Acids

The explosive growth in the number of protein sequences gives rise to the possibility of using the natural variation in sequences of homologous proteins to find residues that control different protein phenotypes. Because in many cases different phenotypes are each controlled by a group of residues, the mutations that separate one version of a phenotype from another will be correlated. Here we incorporate biological knowledge about protein phenotypes and their variability in the sequence alignment of interest into algorithms that detect correlated mutations, improving their ability to detect the residues that control those phenotypes. We demonstrate the power of this approach using simulations and recent experimental data. Applying these principles to the protein families encoded by Dscam and Protocadherin allows us to make testable predictions about the residues that dictate the specificity of molecular interactions

- My Research Is Their Business, but I’m Not Their Business- : Patient and Clinician Perspectives on Commercialization of Precision Oncology Data

BackgroundGenetic sequencing and precision oncology have supported clinical breakthroughs but depend upon access to vast arrays of research specimens and data. One way for academic medical centers to fund such infrastructure and research is - commercialization- of access to specimens and data to industry. Here we explore patient and clinician perspectives regarding cancer specimen and data commercialization with the goal of improving such processes in the future.Materials and MethodsThis qualitative analysis was embedded within a prospective precision oncology sequencing study of adults with head and neck cancer. Via semistructured dyadic interviews with patients with cancer and their doctors, we assessed understanding and concerns regarding potential commercialization, opinions regarding investment of profits, and perspectives regarding the return of information directly to participants from industry.ResultsSeveral patient- and clinician- participants did not understand that the consent form already permitted commercialization of patient genetic data and expressed concerns regarding who would profit from the data, how profits would be used, and privacy and access. Patients were generally more comfortable with commercialization than clinicians. Many patients and clinicians were comfortable with investing profits back into research, but clinicians were more interested in investment in head and neck cancer research specifically. Patients generally supported potential return- of- results from a private entity, but their clinicians were more skeptical.ConclusionOur results illustrate the limitations of mandatory disclosures in the informed consent process. The voices of both patients and their doctors are critical to mitigate violations of privacy and a degradation of trust as stakeholders negotiate the terms of academic and commercial engagement.Implications for PracticeFurther education is needed regarding how and why specimens and data in precision oncology research may be commercialized for both patients and providers alike. This process will require increased transparency, comprehension, and engagement of involved stakeholders.To better understand perspectives on cancer specimen and data commercialization, interviews of patients participating in a prospective precision medicine cancer sequencing study were conducted, along with corresponding interviews with the patients’ referring doctors. This article reports the results and aims to improve the consent process for biospecimen and health data sharing and commercialization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156136/2/onco13272.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156136/1/onco13272_am.pd

Predictors of survival after total laryngectomy for recurrent/persistent laryngeal squamous cell carcinoma

BackgroundTotal laryngectomy remains the treatment of choice for recurrent/persistent laryngeal squamous cell carcinoma (SCC) after radiotherapy (RT) or chemoradiotherapy (CRT). However, despite attempts at aggressive surgical salvage, survival in this cohort remains suboptimal.MethodsA prospectively maintained single‐institution database was queried for patients undergoing total laryngectomy for recurrent/persistent laryngeal SCC after initial RT/CRT between 1998 and 2015(n = 244). Demographic, clinical, and survival data were abstracted. The Kaplan‐Meier survival curves and hazard ratios (HRs) were calculated.ResultsFive‐year overall survival (OS) was 49%. Five‐year disease‐free survival (DFS) was 58%. Independent predictors of OS included severe comorbidity (Adult Comorbidity Evaluation‐27 [ACE‐27] scale; HR 3.76; 95% confidence interval [CI] 1.56‐9.06), and positive recurrent clinical nodes (HR 2.91; 95% CI 1.74‐4.88).ConclusionSevere comorbidity status is the strongest predictor of OS, suggesting that increased attention to mitigating competing risks to health is critical. These data may inform a risk prediction model to allow for focused shared decision making, preoperative health optimization, and patient selection for adjuvant therapies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139972/1/hed24918.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139972/2/hed24918_am.pd

Ten Questions Concerning the Built Environment and Mental Health

Most people spend the majority of their lives indoors. Research over the last thirty years has focused on investigating the mechanisms through which specific elements of the built environment, such as indoor air quality, influence the physical health of occupants. However, similar effort has not been expended in regard to mental health, a significant public health concern. One in five Americans has been diagnosed with a mental health disorder in the past year, and, in the United States, the number of suicide deaths are similar to the number of deaths due to breast cancer. Increases in mental health disorders in Western societies may be due, in part, to increased systemic inflammation, secondary to decreased exposures to a diverse microbial environment (i.e., the hygiene hypothesis, “Old Friends” hypothesis, “missing microbes” hypothesis, or biodiversity hypothesis), as well as increased environmental exposures that lead to chronic low-grade inflammation. In this review, we provide an assessment that integrates historical research across disciplines. We offer ten questions that highlight the importance of current lessons learned regarding the built environment and mental health, including a potential role for the microbiome of the built environment to influence mental health. Suggested areas for future investigation are also highlighted

A Framework for Estimating the United States Depression Burden Attributable to Indoor Fine Particulate Matter Exposure

Recently published exploratory studies based on exposure to outdoor fine particulates, defined as particles with a nominal mean diameter less than or equal to 2.5 μm (PM2.5) indicate that the pollutant may play a role in mental health conditions, such as major depressive disorder. This paper details a model that can estimate the United States (US) major depressive disorder burden attributable to indoor PM2.5 exposure, locally modifiable through input parameter calibrations. By utilizing concentration values in an exposure-response function, along with relative risk values derived from epidemiological studies, the model estimated the prevalence of expected cases of major depressive disorder in multiple scenarios. Model results show that exposure to indoor PM2.5 might contribute to 476,000 cases of major depressive disorder in the US (95% confidence interval 11,000–1,100,000), approximately 2.7% of the total number of cases reported annually. Increasing heating, ventilation, and air conditioning (HVAC) filter efficiency in a residential dwelling results in minor reductions in depressive disorders in rural or urban locations in the US. Nevertheless, a minimum efficiency reporting value (MERV) 13 filter does have a benefit/cost ratio at or near one when smoking occurs indoors; during wildfires; or in locations with elevated outdoor PM2.5 concentrations. The approach undertaken herein could provide a transparent strategy for investment into the built environment to improve the mental health of the occupants

Powered bone marrow biopsy procedures produce larger core specimens, with less pain, in less time than with standard manual devices

Bone marrow sampling remains essential in the evaluation of hematopoietic and many non-hematopoietic disorders. One common limitation to these procedures is the discomfort experienced by patients. To address whether a Powered biopsy system could reduce discomfort while providing equivalent or better results, we performed a randomized trial in adult volunteers. Twenty-six subjects underwent bilateral biopsies with each device. Core samples were obtained in 66.7% of Manual insertions; 100% of Powered insertions (P=0.002). Initial mean biopsy core lengths were 11.1±4.5 mm for the Manual device; 17.0±6.8 mm for the Powered device (P<0.005). Pathology assessment for the Manual device showed a mean length of 6.1±5.6 mm, width of 1.0±0.7 mm, and volume of 11.0±10.8 mm3. Powered device measurements were mean length of 15.3±6.1 mm, width of 2.0±0.3 mm, and volume of 49.1±21.5 mm3 (P<0.001). The mean time to core ejection was 86 seconds for Manual device; 47 seconds for the Powered device (P<0.001). The mean second look overall pain score was 33.3 for the Manual device; 20.9 for the Powered (P=0.039). We conclude that the Powered biopsy device produces superior sized specimens, with less overall pain, in less time

Biosynthesis and enzymology of the Caenorhabditis elegans cuticle: identification and characterization of a novel serine protease inhibitor.

The nematode Caenorhabditis elegans represents an excellent model in which to examine nematode gene expression and function. A completed genome, straightforward transgenesis, available mutants and practical genome-wide RNAi approaches provide an invaluable toolkit in the characterization of nematode genes. We have performed a targeted RNAi screen in an attempt to identify components of the cuticle collagen biosynthetic pathway. Collagen biosynthesis and cuticle assembly are multi-step processes that involve numerous key enzymes involved in post-translational modification, trimer folding, procollagen processing and subsequent cross-linking stages. Many of these steps, the modifications and the enzymes are unique to nematodes and may represent attractive targets for the control of parasitic nematodes. A novel serine protease inhibitor was uncovered during our targeted screen, which is involved in collagen maturation, proper cuticle assembly and the moulting process. We have confirmed a link between this inhibitor and the previously uncharacterized bli-5 locus in C. elegans. The mutant phenotype, spatial expression pattern and the over-expression phenotype of the BLI-5 protease inhibitor and their relevance to collagen biosynthesis are discussed

Effect of afterload alterations on the functional border zone measured with two-dimensional echocardiography during acute coronary occlusion

In the setting of acute myocardial infarction, pharmacologic intervention resulting in afterload changes are common but the effect of these changes on regional left ventricular function, and specifically the functional border zone, has not been fully investigated. Accordingly, we studied the effects of afterload manipulation on circumferential flow-function relationships and the functional border zone in 16 open-chest, anesthetized dogs. During left circumflex coronary artery occlusion, eight animals were infused with phenylephrine to increase afterload; eight others received nitroprusside for afterload reduction. Following coronary artery occlusion, subendocardial blood flow and wall thickening decreased in the ischemic zone (p p = ns). Similarly, when blood pressure was increased by 47%, the extent of the functional border zone did not change (32 +/- 10 degrees vs 37 +/- 10 degrees). Therefore circumferential flow-function relations and the spatial extent of the functional border zone are not altered by changing afterload during acute left circumflex coronary artery occlusion in this model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27132/1/0000125.pd