Superconductor-sapphire cavity for an all-cryogenic SCSO

To develop a superconducting cavity stabilized oscillator (SCSO) as a frequency standard, we are studying the properties of cavities consisting of a single crystal of sapphire surrounded by a superconducting film. Measurements of quality factors of spherical and cylindrical samples of sapphire are reported. Loss values less than 2 × 10^-9 have been measured at a temperature of 1.45K. A design for an all-cryogenic SCSO is described, with particular emphasis on the cavity requirements. We conclude that such a design would allow greatly enhanced stability of operation due substantially to the thermal and physical properties of the sapphire substrate. Cavity Q requirements are relatively modest, with better than 10^-16 frequency stability predicted for a Q of 10^8

Lineage dynamics of murine pancreatic development at single-cell resolution.

Organogenesis requires the complex interactions of multiple cell lineages that coordinate their expansion, differentiation, and maturation over time. Here, we profile the cell types within the epithelial and mesenchymal compartments of the murine pancreas across developmental time using a combination of single-cell RNA sequencing, immunofluorescence, in situ hybridization, and genetic lineage tracing. We identify previously underappreciated cellular heterogeneity of the developing mesenchyme and reconstruct potential lineage relationships among the pancreatic mesothelium and mesenchymal cell types. Within the epithelium, we find a previously undescribed endocrine progenitor population, as well as an analogous population in both human fetal tissue and human embryonic stem cells differentiating toward a pancreatic beta cell fate. Further, we identify candidate transcriptional regulators along the differentiation trajectory of this population toward the alpha or beta cell lineages. This work establishes a roadmap of pancreatic development and demonstrates the broad utility of this approach for understanding lineage dynamics in developing organs

On variational solutions for whole brain serial-section histology using a Sobolev prior in the computational anatomy random orbit model

This paper presents a variational framework for dense diffeomorphic atlas-mapping onto high-throughput histology stacks at the 20 mum meso-scale. The observed sections are modelled as Gaussian random fields conditioned on a sequence of unknown section by section rigid motions and unknown diffeomorphic transformation of a three-dimensional atlas. To regularize over the high-dimensionality of our parameter space (which is a product space of the rigid motion dimensions and the diffeomorphism dimensions), the histology stacks are modelled as arising from a first order Sobolev space smoothness prior. We show that the joint maximum a-posteriori, penalized-likelihood estimator of our high dimensional parameter space emerges as a joint optimization interleaving rigid motion estimation for histology restacking and large deformation diffeomorphic metric mapping to atlas coordinates. We show that joint optimization in this parameter space solves the classical curvature non-identifiability of the histology stacking problem. The algorithms are demonstrated on a collection of whole-brain histological image stacks from the Mouse Brain Architecture Project

Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement

Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co-morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve-dependent mechanism

Trends in non-metastatic prostate cancer management in the Northern and Yorkshire region of England, 2000–2006

Background: Our objective was to analyse variation in non-metastatic prostate cancer management in the Northern and Yorkshire region of England. Methods: We included 21 334 men aged ⩾55, diagnosed between 2000 and 2006. Principal treatment received was categorised into radical prostatectomy (11%), brachytherapy (2%), external beam radiotherapy (16%), hormone therapy (42%) and no treatment (29%). Results: The odds ratio (OR) for receiving a radical prostatectomy was 1.53 in 2006 compared with 2000 (95% CI 1.26–1.86), whereas the OR for receiving hormone therapy was 0.57 (0.51–0.64). Age was strongly associated with treatment received; radical treatments were significantly less likely in men aged ⩾75 compared with men aged 55–64 years, whereas the odds of receiving hormone therapy or no treatment were significantly higher in the older age group. The OR for receiving radical prostatectomy, brachytherapy or external beam radiotherapy were all significantly lower in the most deprived areas when compared with the most affluent (0.64 (0.55–0.75), 0.32 (0.22–0.47) and 0.83 (0.74–0.94), respectively) whereas the OR for receiving hormone therapy was 1.56 (1.42–1.71). Conclusions: This study highlights the variation and inequalities that exist in the management of non-metastatic prostate cancer in the Northern and Yorkshire region of England

Urinary Diversion for Severe Urinary Adverse Events of Prostate Radiation: Results from a Multi-Institutional Study

PurposeWe evaluated the short and long-term surgical outcomes of urinary diversion done for urinary adverse events arising from prostate radiation therapy. We hypothesized that patient characteristics are associated with complications after urinary diversion.Materials and methodsWe performed a retrospective cohort study of 100 men who underwent urinary diversion (urinary conduit or continent catheterizable pouch) due to urinary adverse events after prostate radiotherapy from 2007 to 2016 from 9 academic centers in the United States. Outcome measurements included predictors of short and long-term complications, and readmission after urinary diversion of patients who had prostate cancer treated with radiotherapy. The data were summarized using descriptive statistics and univariate associations with complications were identified with logistic regression controlling for center.ResultsMean patient age was 71 years and median time from radiotherapy to urinary diversion was 8 years. Overall 81 (81%) patients had combined modality therapy (radical prostatectomy plus radiotherapy or various combinations of radiotherapy). Grade 3a or greater Clavien-Dindo complications occurred in 31 (35%) men, including 4 deaths (4.5%). Normal weight men had more short-term complications compared to overweight (OR 4.9, 95% CI 1.3-23.1, p=0.02) and obese men (OR 6.3, 95% CI 1.6-31.1, p=0.009). Hospital readmission within 6 weeks of surgery occurred for 35 (38%) men. Surgery was needed to treat long-term complications after urinary diversion in 19 (22%) patients with a median followup of 16.3 months.ConclusionsUrinary diversion after prostate radiotherapy has a considerable short and long-term surgical complication rate. Urinary diversion most often cannot be avoided in these patients but appreciation of the risks allows for informed shared decision making between surgeons and patients

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy