Responsible, practical genomic data sharing that accelerates research.

Data sharing anchors reproducible science, but expectations and best practices are often nebulous. Communities of funders, researchers and publishers continue to grapple with what should be required or encouraged. To illuminate the rationales for sharing data, the technical challenges and the social and cultural challenges, we consider the stakeholders in the scientific enterprise. In biomedical research, participants are key among those stakeholders. Ethical sharing requires considering both the value of research efforts and the privacy costs for participants. We discuss current best practices for various types of genomic data, as well as opportunities to promote ethical data sharing that accelerates science by aligning incentives.

Recent Advances and Emerging Applications in Text and Data Mining for Biomedical Discovery.

Precision medicine will revolutionize the way we treat and prevent disease. A major barrier to the implementation of precision medicine that clinicians and translational scientists face is understanding the underlying mechanisms of disease. We are starting to address this challenge through automatic approaches for information extraction, representation and analysis. Recent advances in text and data mining have been applied to a broad spectrum of key biomedical questions in genomics, pharmacogenomics and other fields. We present an overview of the fundamental methods for text and data mining, as well as recent advances and emerging applications toward precision medicine.

Adapting bioinformatics curricula for big data.

Modern technologies are capable of generating enormous amounts of data that measure complex biological systems. Computational biologists and bioinformatics scientists are increasingly being asked to use these data to reveal key systems-level properties. We review the extent to which curricula are changing in the era of big data. We identify key competencies that scientists dealing with big data are expected to possess across fields, and we use this information to propose courses to meet these growing needs. While bioinformatics programs have traditionally trained students in data-intensive science, we identify areas of particular biological, computational and statistical emphasis important for this era that can be incorporated into existing curricula. For each area, we propose a course structured around these topics, which can be adapted in whole or in parts into existing curricula. In summary, specific challenges associated with big data provide an important opportunity to update existing curricula, but we do not foresee a wholesale redesign of bioinformatics training programs.

Leveraging real-world data to predict cancer cachexia stage, quality of life, and survival in a racially and ethnically diverse multi-institutional cohort of treatment-naïve patients with pancreatic ductal adenocarcinoma.

Introduction: Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management. Objectives: The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS). Materials and methods: A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations. Results: CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS. Conclusions: Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

Are the Pieces Starting to Come Together for Management of Desmoid Tumors?

Desmoid tumor research is changing how desmoid tumors are managed with the prospective documentation that growing desmoid tumors spontaneously regress one third of the time. Patient partnership through the Desmoid Research Tumor Foundation and academia is leading to rapid advancement in desmoid tumor biology understanding and treatment. See related articles by Colombo et al., p. 4027, Nathenson et al., p. 4092, and Penel et al., p. 4105.

Thermal decomposition of meso- and d,l-3,4-diethyl-3,4-dimethyldiazetine N,N'-dioxide.

Two stereochemically defined diazetine N,N'-dioxides were synthesized. Thermal decomposition at 200 degrees C resulted in 95% retention of stereochemistry in the alkene product relative to the starting stereochemistry. These results suggest that decomposition occurs via cleavage of the two C-N bonds either simultaneously or in rapid succession.

Refining environmental enrichment to advance rehabilitation based research after experimental traumatic brain injury.

The typical environmental enrichment (EE) paradigm, which consists of continuous exposure after experimental traumatic brain injury (TBI), promotes behavioral and histological benefits. However, rehabilitation is often abbreviated in the clinic and administered in multiple daily sessions. While recent studies have demonstrated that a once daily 6-hr bout of EE confers benefits comparable to continuous EE, breaking the therapy into two shorter sessions may increase novelty and ultimately enhance recovery. Hence, the aim of the study was to test the hypothesis that functional and histological outcomes will be significantly improved by daily preclinical neurorehabilitation consisting of two 3-hr periods of EE vs. a single 6-hr session. Anesthetized adult male rats received a controlled cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and were then randomly assigned to groups receiving standard (STD) housing, a single 6-hr session of EE, or two 3-hr sessions of EE daily for 3weeks. Motor function (beam-balance/traversal) and acquisition of spatial learning/memory retention (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. Both EE conditions improved motor function and acquisition of spatial learning, and reduced cortical lesion volume relative to STD housing (p<0.05), but did not differ from one another in any endpoint (p>0.05). The findings replicate previous work showing that 6-hr of EE daily is sufficient to confer behavioral and histological benefits after TBI and extend the findings by demonstrating that the benefits are comparable regardless of how the 6-hrs of EE are accrued. The relevance of the finding is that it can be extrapolated to the clinic and may benefit patients who cannot endure a single extended period of neurorehabilitation.

Comparable impediment of cognitive function in female and male rats subsequent to daily administration of haloperidol after traumatic brain injury.

Antipsychotic drugs, such as haloperidol (HAL), are prescribed in the clinic to manage traumatic brain injury (TBI)-induced agitation. While preclinical studies have consistently shown that once-daily administration of HAL hinders functional recovery after TBI in male rats, its effects in females are unknown. Hence, the objective of this study was to directly compare neurobehavioral and histological outcomes in both sexes to determine whether the reported deleterious effects of HAL extend to females. Anesthetized adult female and male rats received either a controlled cortical impact (CCI) or sham injury and then were randomly assigned to a dosing regimen of HAL (0.5mg/kg, i.p.) or vehicle (VEH; 1mL/kg, i.p.) that was initiated 24h after injury and continued once daily for 19 consecutive days. Motor function was tested using established beam-balance/walk protocols on post-operative days 1-5 and acquisition of spatial learning was assessed with a well-validated Morris water maze task on days 14-19. Cortical lesion volume was quantified at 21days. No statistical differences were revealed between the HAL and VEH-treated sham groups and thus they were pooled for each sex. HAL only impaired motor recovery in males (p<0.05), but significantly diminished spatial learning in both sexes (p<0.05). Females, regardless of treatment, exhibited smaller cortical lesions vs VEH-treated males (p<0.05). Taken together, the data show that daily HAL does not prohibit motor recovery in females, but does negatively impact cognition. These task-dependent differential effects of HAL in female vs male rats may have clinical significance as they can direct therapy.

Sleep duration is associated with survival in advanced cancer patients.

OBJECTIVE: Sleep problems have been linked to increased risk of mortality in the general population. Limited evidence suggests similar relationships among people diagnosed with cancer. The aims of the present study were to investigate the type and rates of sleep problems in advanced cancer patients and examine whether sleep problems are associated with survival. METHODS: A prospective study of 292 patients with advanced cancers affecting the hepatobiliary and pancreatic systems were administered a battery of questionnaires measuring sociodemographic information, sleep, and depression. Descriptive statistics, ANOVA, Chi-square, Kaplan-Meier survival, and Cox regression analyses were performed to test the aims. RESULTS: The majority of patients were male (64%) and the mean age was 62 years (SD = 11). Fifty-nine percent of patients reported poor sleep quality; 43% reported sleeping ≤6 h and 2% ≥10 h; 40% reported sleep latency of 30 min or greater; average sleep efficiency was 80%. Of the 292 patients, 58% reported clinically levels of depression and depressive symptoms were related to shorter sleep duration (p = 0.02). After adjusting for factors known to contribute to survival, a curvilinear relationship was observed between sleep duration and mortality: short and long sleep duration were associated with increased mortality [linear term: hazard ratio (HR) = 0.485, 95% confidence interval (CI) = 0.275-0.857; quadratic term: HR = 1.064, 95% CI = 1.015-1.115]. CONCLUSIONS: Consistent with findings in the general population, a curvilinear relationship between sleep duration and mortality was observed in advanced cancer patients. The high prevalence of sleep problems and link with mortality warrants routine screening and development of evidence-based treatments for sleep problems in the oncology setting.

Inadequate prenatal care and elevated blood lead levels among children born in Providence, Rhode Island: a population-based study.

OBJECTIVE: This study was conducted to determine whether children born to mothers receiving inadequate prenatal care are at an increased risk for having an elevated blood lead level during early childhood. METHODS: The authors conducted a population-based study of children born in Providence, Rhode Island, from 1997 to 2001 whose mothers had received adequate, intermediate, or inadequate prenatal care. The children's blood lead levels were compared between groups using bivariate and logistic regression. To understand the regulatory implications and public health impact of changing the definition of an elevated blood lead level, "elevated" was defined as 5 microg/dL, 10 microg/dL, and 15 microg/dL. RESULTS: Children born to mothers who received inadequate prenatal care were at an elevated risk for having an elevated blood lead level later in life. This relationship remained statistically significant for each definition of elevated blood lead level and after controlling for other socio-economic status measures and birthweight (at 5 microg/dL, odds ratio [OR] = 1.36, 95% confidence interval [CI] 1.09, 1.68, p = 0.006; at 10 microg/dL, OR = 1.68, 95% CI 1.26, 2.24, p < 0.0004; at 15 microg/dL, OR = 1.83, 95% CI 1.10, 3.04, p = 0.019) represent an opportune moment to identify expectant mothers living in lead-contaminated environments. CONCLUSIONS: Results suggest that conducting lead screening as a regular part of prenatal care provision could help identify women possibly experiencing ongoing lead exposure and help reduce or prevent exposures to their offspring.

Training the next generation of quantitative biologists in the era of big data.

The following sections are included: Workshop Focus, Workshop Contributions and References.

Scientific controversy and asbestos: making disease invisible.

Despite irrefutable evidence that asbestos causes asbestosis, lung cancer, and mesothelioma, asbestos mining, milling, and manufacturing continue. The authors discuss three scientific debates over the roles of fiber types, viruses, and genetics in the development of mesothelioma. While these controversies might appear internal to science and unconnected to policies of the global asbestos industry, they argue that scientific debates, whether or not fostered by industry, play a central role in shaping conceptualization of the problem of asbestos-related disease. In South Africa, India, and elsewhere, these controversies help to make the disease experience of asbestos-exposed workers and people in asbestos-contaminated communities invisible, allowing the asbestos industry to escape accountability for its practices.

Building the next generation of quantitative biologists.

Many colleges and universities across the globe now offer bachelors, masters, and doctoral degrees, along with certificate programs in bioinformatics. While there is some consensus surrounding curricula competencies, programs vary greatly in their core foci, with some leaning heavily toward the biological sciences and others toward quantitative areas. This allows prospective students to choose a program that best fits their interests and career goals. In the digital age, most scientific fields are facing an enormous growth of data, and as a consequence, the goals and challenges of bioinformatics are rapidly changing; this requires that bioinformatics education also change. In this workshop, we seek to ascertain current trends in bioinformatics education by asking the question, "What are the core competencies all bioinformaticians should have at the end of their training, and how successful have programs been in placing students in desired careers?"

Poly(Acrylic Acid-b-Styrene) Amphiphilic Multiblock Copolymers as Building Blocks for the Assembly of Discrete Nanoparticles.

In order to expand the utility of current polymeric micellar systems, we have developed amphiphilic multiblock copolymers containing alternating blocks of poly(acrylic acid) and poly(styrene). Heterotelechelic poly(tert-butyl acrylate-b-styrene) diblock copolymers containing an α-alkyne and an ω-azide were synthesized by atom transfer radical polymerization (ATRP), allowing control over the molecular weight while maintaining narrow polydispersity indices. The multiblock copolymers were constructed by copper-catalyzed azide-alkyne cycloaddition of azide-alkyne end functional diblock copolymers which were then characterized by (1)H NMR, FT-IR and SEC. The tert-butyl moieties of the poly(tert-butyl acrylate-b-styrene) multiblock copolymers were easily removed to form the poly(acrylic acid-b-styrene) multiblock copolymer ((PAA-PS)(9)), which contained up to 9 diblock repeats. The amphiphilic multiblock (PAA-PS)(9) (M(n) = 73.3 kg/mol) was self-assembled by dissolution into tetrahydrofuran and extensive dialysis against deionized water for 4 days. The critical micelle concentration (CMC) for (PAA-PS)(9) was determined by fluorescence spectroscopy using pyrene as a fluorescent probe and was found to be very low at 2 × 10(-4) mg/mL. The (PAA-PS)(9) multiblock was also analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The hydrodynamic diameter of the particles was found to be 11 nm. Discrete spherical particles were observed by TEM with an average particle diameter of 14 nm. The poly(acrylic acid) periphery of the spherical particles should allow for future conjugation of biomolecules.