Enhanced cancer therapy with cold-controlled drug release and photothermal warming enabled by one nanoplatform

Stimuli-responsive nanoparticles hold great promise for drug delivery to improve the safety and efficacy of cancer therapy. One of the most investigated stimuli-responsive strategies is to induce drug release by heating with laser, ultrasound, or electromagnetic field. More recently, cryosurgery (also called cryotherapy and cryoablation), destruction of diseased tissues by first cooling/freezing and then warming back, has been used to treat various diseases including cancer in the clinic. Here we developed a cold-responsive nanoparticle for controlled drug release as a result of the irreversible disassembly of the nanoparticle when cooled to below ∼10 °C. Furthermore, this nanoparticle can be used to generate localized heating under near infrared (NIR) laser irradiation, which can facilitate the warming process after cooling/freezing during cryosurgery. Indeed, the combination of this cold-responsive nanoparticle with ice cooling and NIR laser irradiation can greatly augment cancer destruction both in vitro and in vivo with no evident systemic toxicity

Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy

Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy but severely limited by the availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic Zucker/SHHF F1 hybrid (ZS) female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 wk of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 wk of age. Rats were euthanized at 34 wk of age. IRCT with cells expressing serum amyloid A had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 wk after the second infusion. The results indicate that IRCT with serum amyloid A-positive cells is effective in preventing the progression of chronic kidney disease in rats with diabetic and ischemic nephropathy

Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease

AbstractThree-dimensional tissue-structural relationships are not well captured by typical thin-section histology, posing challenges for the study of tissue physiology and pathology. Moreover, while recent progress has been made with intact methods for clearing, labeling, and imaging whole organs such as the mature brain, these approaches are generally unsuitable for soft, irregular, and heterogeneous tissues that account for the vast majority of clinical samples and biopsies. Here we develop a biphasic hydrogel methodology, which along with automated analysis, provides for high-throughput quantitative volumetric interrogation of spatially-irregular and friable tissue structures. We validate and apply this approach in the examination of a variety of developing and diseased tissues, with specific focus on the dynamics of normal and pathological pancreatic innervation and development, including in clinical samples. Quantitative advantages of the intact-tissue approach were demonstrated compared to conventional thin-section histology, pointing to broad applications in both research and clinical settings.</jats:p

A Distance-Weighted Interaction Map Reveals a Previously Uncharacterized Layer of the Bacillus subtilis Spore Coat

SummaryBacillus subtilis spores are encased in a protein assembly called the spore coat that is made up of at least 70 different proteins. Conventional electron microscopy shows the coat to be organized into two distinct layers. Because the coat is about as wide as the theoretical limit of light microscopy, quantitatively measuring the localization of individual coat proteins within the coat is challenging. We used fusions of coat proteins to green fluorescent protein to map genetic dependencies for coat assembly and to define three independent subnetworks of coat proteins. To complement the genetic data, we measured coat protein localization at subpixel resolution and integrated these two data sets to produce a distance-weighted genetic interaction map. Using these data, we predict that the coat comprises at least four spatially distinct layers, including a previously uncharacterized glycoprotein outermost layer that we name the spore crust. We found that crust assembly depends on proteins we predicted to localize to the crust. The crust may be conserved in all Bacillus spores and may play critical functions in the environment

MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.

A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors

Inferring More from Less: Prospector as a Photometric Redshift Engine in the Era of JWST

The advent of the James Webb Space Telescope (JWST) signals a new era in exploring galaxies in the high-$z$ universe. Current and upcoming JWST imaging will potentially detect galaxies out to $z \sim 20$, creating a new urgency in the quest to infer accurate photometric redshifts (photo-$z$) for individual galaxies from their spectral energy distributions, as well as masses, ages and star formation rates. Here we illustrate the utility of informed priors encoding previous observations of galaxies across cosmic time in achieving these goals. We construct three joint priors encoding empirical constraints of redshifts, masses, and star formation histories in the galaxy population within the \prospector\ Bayesian inference framework. In contrast with uniform priors, our model breaks an age-mass-redshift degeneracy, and thus reduces the mean bias error in masses from 0.3 to 0.1 dex, and in ages from 0.6 to 0.2 dex in tests done on mock JWST observations. Notably, our model recovers redshifts at least as accurately as the state-of-the-art photo-$z$ code \eazy\ in deep JWST fields, but with two advantages: tailoring a model based on a particular survey renders mostly unnecessary given well-motivated priors; obtaining joint posteriors describing stellar, active galactic nuclei, gas, and dust contributions becomes possible. We can now confidently use the joint distribution to propagate full non-Gaussian redshift uncertainties into inferred properties of the galaxy population. This model, ``\prospector-$\beta$'', is intended for fitting galaxy photometry where the redshift is unknown, and will be instrumental in ensuring the maximum science return from forthcoming photometric surveys with JWST. The code is made publicly available online as a part of \prospector.Comment: Accepted for publication in ApJL. 13 pages, 6 figures, 2 tables. The code is made publicly available online as a part of Prospector; the version used in this work corresponds to the state of the Git repository at commit 820ad7

Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity

Abstract Background Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models. Methods In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells. Results We show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG-associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity. Conclusions We propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers

A longitudinal implementation evaluation of a physical activity program for cancer survivors: LIVESTRONG(R) at the YMCA

Purpose: Increased physical activity (PA) levels in cancer survivors are associated with decreased risk of recurrence and mortality as well as additional positive health outcomes. PA interventions have shown to be efficacious, though many lack translation to and sustainability in community settings. We used dimensions of the RE-AIM framework to evaluate LIVESTRONG(R) at the YMCA, a nation-wide community-based PA program for cancer survivors delivered at Ys. Methods: This was a longitudinal study design using national LIVESTRONG at the YMCA data compiled between 2010 and 2018. Data is from all YMCAs who deliver LIVESTRONG at the YMCA, submitted by Program Directors to the YMCA-USA. We assessed reach (number of participants), adoption (associations offering the program), implementation (conducting 3 fidelity checks), and organizational level maintenance (associations recently offering program). We also examined relationships between organizational characteristics (years of program existence and association area household income) and program implementation factors with member conversion rates. Results: As of 2018, LIVESTRONG at the YMCA has reached 62,044 survivors and 245 of the 840 (29.2%) of Y associations have adopted the program. Among the adopters, 91% were aware of fidelity checks; implementation of observational (62.3%), goal setting (49.9%), and functional (64.6%) checklists varied. Most (95.1%) adopters reported offering \u3e /= 1 LIVESTRONG session per year (organizational-level maintenance) and a facility-level mean membership conversion percentage of 46.9 +/- 31.2%. Fewer years implementing the program and higher association area household income were significantly associated with a greater membership conversion rate vs their comparison. In a multiple regression model controlling for organizational characteristics, conducting the fidelity checks independently (observational, beta = 8.41; goal-setting, beta = 9.70; and functional, beta = 9.61) and collectively (beta = 10.82; 95% CI 5.90-16.80) was positively associated with higher membership conversion rates. Conclusions: LIVESTRONG at the YMCA, in its early years, has shown promise for high reach, while adoption at more associations could be facilitated. Implementing fidelity checks along with organizational characteristics were associated with membership conversion rate. Identification of association-level strategies to increase reach, adoption, implementation, and maintenance may increase the impact of this community-based PA program