Abstract Extracellular matrix (ECM) is an essential and dynamic component of all tissues and directly affects cellular behavior by providing both mechanical and biochemical signaling cues. Changes in ...ECM can alter tissue homeostasis, potentially leading to promotion of cellular transformation and the generation of tumors. Therefore, understanding ECM compositional changes during cancer progression is vital to the development of targeted treatments. Previous efforts to reproduce the native 3D cellular microenvironment have utilized protein gels and scaffolds that incompletely recapitulate the complexity of native tissues. Here, we address this problem by extracting and comparing ECM from normal human colon and colon tumor that had metastasized to liver. We found differences in protein composition and stiffness, and observed significant differences in vascular network formation and tumor growth in each of the reconstituted matrices, both in vitro and in vivo . We studied free/bound ratios of NADH in the tumor and endothelial cells using Fluorescence Lifetime Imaging Microscopy as a surrogate for the metabolic state of the cells. We observed that cells seeded in tumor ECM had higher relative levels of free NADH, consistent with a higher glycolytic rate, than those seeded in normal ECM. These results demonstrate that the ECM plays an important role in the growth of cancer cells and their associated vasculature.
Palliative care has been one of the most rapidly growing fields of health care in the United States in the past decade. The benefits of palliative care have now been shown in multiple clinical ...trials, with increased patient and provider satisfaction, equal or better symptom control, more discernment of and honoring choices about place of death, fewer and less intensive hospital admissions in the last month of life, less anxiety and depression, less caregiver distress, and cost savings. The cost savings come from cost avoidance, or movement of a patient from a high cost setting to a lower cost setting. Barriers to expanded use include physician resistance, unrealistic expectations of patients and families, and lack of workforce. The future of palliative care includes more penetration into other fields such as nephrology, neurology, and surgery; further discernment of the most effective and cost-effective models; and establishment of more outpatient services.
The COVID-19 pandemic has had a profound impact on health professionals, adding to the moral suffering and burnout that existed prepandemic. The physical, psychological, and moral toll of the ...pandemic has threatened the well-being and integrity of clinicians. The narrative of self-sacrifice and heroism bolstered people early on but was not sustainable over time. For health professions students, the learning environment changed dramatically, limiting opportunities in direct patient care and raising concerns for meeting training requirements. Learners lost social connections and felt isolated while learning remotely, and they witnessed ethical tensions between patient-centered care and parallel obligations to public health. Worries about transmission of the virus and uncertainty about its management contributed to their moral suffering. Educators adjusted curricula to address the changing ethical landscape. Preparing learners for the realities of their future professional identities requires creation of interprofessional moral communities that provide support and help develop the moral agency and integrity of its members using experiential and relational learning methods. Investing in the well-being and resilience of clinicians, implementing the recommendations of the National Academy of Medicine, and engaging learners and faculty as cocreators of ethical practice have the potential to transform the learning environment. Faculty need to be trained as effective mentors to create safe spaces for exploring challenges and address moral adversity. Ethics education will need to expand to issues related to health systems science, social determinants of health, and public health, and the cultivation of moral sensitivity, character development, professional identity formation, and moral resilience.
Top government officials were among the first people vaccinated against Covid-19 in the United States. But prioritization frameworks do not grant government leaders special status, and giving them ...priority raises important questions of fairness and transparency.
Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at ...the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction data and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancement.
Online curricula can make high-quality health professions education accessible in virtually any setting. They can enhance teaching and learning by both standardizing curricular resources and ...individualizing curricular experiences. Despite growing demand for and institutional interest in online curricula for medical education, many medical educators lack a framework for online curriculum development. Without rigorous and thoughtful development, online curricula can waste opportunity and resources by leading to education that is inferior to traditional methods. In this article, the authors describe a systematic approach to online curriculum development based on the Six-Step Approach for Curriculum Development for Medical Education, a widely used method that has led to successful implementation of a variety of traditional and online curricula. In each step, special considerations for curricula with larger and more diverse learner audiences—characteristic of many online curricula—are highlighted. Four common online curricular formats are also discussedblended curricula, instructor-led fully online curricula, self-paced modules, and massive open online courses (MOOCs). The authors emphasize factors that differentiate one online format from another, including the budgetary, technical, and human resource requirements for each. The article concludes by urging medical educators to pursue opportunities to study and disseminate online curricular work.
The pharmacist and medical aid in dying Hughes, Mark T
American journal of health-system pharmacy,
2017-August-15, 2017-Aug-15, 2017-08-15, 20170815, Letnik:
74, Številka:
16
Journal Article
Recenzirano
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Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The use of peptides to nucleate, grow, and stabilize nanoparticles in aqueous media via noncovalent interactions offers new possibilities for creating functional, water-dispersed inorganic/organic ...hybrid materials, particularly for Au nanoparticles. Numerous previous studies have identified peptide sequences that both possess a strong binding affinity for Au surfaces and are capable of supporting nanoparticle growth in water. However, recent studies have shown that not all such peptide sequences can produce stable dispersions of these nanoparticles. Here, via integrated experiments and molecular modeling, we provide new insights into the many factors that influence Au nanoparticle growth and stabilization in aqueous media. We define colloidal stability by the absence of visible precipitation at least 24 h after synthesis. We use binding affinity measurements, nanoparticle synthesis, characterization and stabilization assays, and molecular modeling to investigate a set of sequences based on two known peptides with a strong affinity for Au. This set of biomolecules is designed to probe specific sequence and context effects using both point mutations and global reorganization of the peptides. Our data confirm, for a broader range of sequences, that Au nanoparticle/peptide binding affinity alone is not predictive of peptide-mediated colloidal stability. By comparing nanoparticle stabilization assay outcomes with molecular simulations, we establish a correlation between the colloidal stability of the Au nanoparticles and the degree of conformational diversity in the surface-adsorbed peptides. Our findings suggest future routes to engineer peptide sequences for biobased growth and dispersion of functional nanoparticles in aqueous media.
Controllable 3D assembly of multicomponent inorganic nanomaterials by precisely positioning two or more types of nanoparticles to modulate their interactions and achieve multifunctionality remains a ...major challenge. The diverse chemical and structural features of biomolecules can generate the compositionally specific organic/inorganic interactions needed to create such assemblies. Toward this aim, we studied the materials-specific binding of peptides selected based upon affinity for Ag (AgBP1 and AgBP2) and Au (AuBP1 and AuBP2) surfaces, combining experimental binding measurements, advanced molecular simulation, and nanomaterial synthesis. This reveals, for the first time, different modes of binding on the chemically similar Au and Ag surfaces. Molecular simulations showed flatter configurations on Au and a greater variety of 3D adsorbed conformations on Ag, reflecting primarily enthalpically driven binding on Au and entropically driven binding on Ag. This may arise from differences in the interfacial solvent structure. On Au, direct interaction of peptide residues with the metal surface is dominant, while on Ag, solvent-mediated interactions are more important. Experimentally, AgBP1 is found to be selective for Ag over Au, while the other sequences have strong and comparable affinities for both surfaces, despite differences in binding modes. Finally, we show for the first time the impact of these differences on peptide mediated synthesis of nanoparticles, leading to significant variation in particle morphology, size, and aggregation state. Because the degree of contact with the metal surface affects the peptide’s ability to cap the nanoparticles and thereby control growth and aggregation, the peptides with the least direct contact (AgBP1 and AgBP2 on Ag) produced relatively polydispersed and aggregated nanoparticles. Overall, we show that thermodynamically different binding modes at metallic interfaces can enable selective binding on very similar inorganic surfaces and can provide control over nanoparticle nucleation and growth. This supports the promise of bionanocombinatoric approaches that rely upon materials recognition.
Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight ...inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10−6). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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