Citations

Summary Background and Purpose Sprawling ( Swl ) is a radiation‐induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1 ). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. Methods and Results To display the phenotype of Swl mutant mice, we examined the embryos of homozygous ( Swl/Swl ) and heterozygous ( Swl /+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl /+ mice. The Swl /+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/ + DRG neurons was revealed during E11.5–E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein‐driven nerve growth factor (NGF). Mitochondria, another dynein‐driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild‐type (WT) neurons. Nevertheless, the Swl , Loa, and Cra mutations did not affect homodimerization of DYNC1H1. Conclusion The Swl/Swl mutation of Dync1h1 gene led to embryonic mal‐development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein‐driven cargos and excessive apoptosis during mid‐ to late‐developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1.

Biomechanical evaluation of the subsynovial connective tissue (SSCT) provides insight into the causes of carpal tunnel syndrome. Studies of carpal tunnel mechanics have been performed using fresh-frozen cadaver tissue. Freezing can affect mechanical properties of some tissues, but its effect on SSCT is unknown. A total of 16 rabbit paws were harvested from eight New Zealand rabbits and subjected to mechanical testing consisting of three repeated tendon excursions in sets of three different excursion magnitudes. One paw from each animal was unfrozen. The contralateral paw was frozen and thawed before testing. Force, energy and stiffness of the first cycle of each set were evaluated, as were ratios of the second to first cycle for each parameter. Two-factor ANOVA with repeated measures over both factors was performed. No significant interactions between factors were found. There were no significant differences between fresh and frozen paws for any parameters, though there were significant differences between excursion amplitudes. The damage threshold was not different between fresh and frozen paws. This study demonstrated that freezing rabbit subsynovial connective tissue does not significantly change its mechanical properties. The same may be true for human cadaver tissues. Results of cadaver mechanical testing may not be influenced by this preservation technique.

Deleting neuronal heparan sulfates in a mouse model of Alzheimer’s disease results in faster Aβ clearance, reduced Aβ aggregation, and less amyloid pathology.

Functional FOXA1 targeting is mostly unique to each of the four human cancer cell lines HepG2, LNCaP, MCF7, and T47D.

Spine intersegmental motion parameters and the resultant regional patterns may be useful for biomechanical classification of low back pain (LBP) as well as assessing the appropriate intervention strategy. Because of its availability and reasonable cost, two-dimensional (2D) fluoroscopy has great potential as a diagnostic and evaluative tool. However, the technique of quantifying intervertebral motion in the lumbar spine must be validated, and the sensitivity assessed. The purpose of this investigation was to (1) compare synchronous fluoroscopic and optoelectronic measures of intervertebral rotations during dynamic flexion–extension movements in vitro and (2) assess the effect of C-arm rotation to simulate off-axis patient alignment on intervertebral kinematics measures. Six cadaveric lumbar–sacrum specimens were dissected, and active marker optoelectronic sensors were rigidly attached to the bodies of L2–S1. Fluoroscopic sequences and optoelectronic kinematic data (0.15-mm linear, 0.17–0.20 deg rotational, accuracy) were obtained simultaneously. After images were obtained in a true sagittal plane, the image receptor was rotated in 5 deg increments (posterior oblique angulations) from 5 deg to 15 deg. Quantitative motion analysis (qma) software was used to determine the intersegmental rotations from the fluoroscopic images. The mean absolute rotation differences between optoelectronic values and dynamic fluoroscopic values were less than 0.5 deg for all the motion segments at each off-axis fluoroscopic rotation and were not significantly different (P > 0.05) for any of the off-axis rotations of the fluoroscope. Small misalignments of the lumbar spine relative to the fluoroscope did not introduce measurement variation in relative segmental rotations greater than that observed when the spine and fluoroscope were perpendicular to each other, suggesting that fluoroscopic measures of relative segmental rotation during flexion–extension are likely robust, even when patient alignment is not perfect.

Summary The transcription factor forkhead box protein A1 (FOXA1) plays a critical role in the proliferation of human breast cancer cells, particularly estrogen receptor alpha (ERα)‐positive luminal breast cancer cells. However, genetic studies of the requirement for Foxa1 in mammary tumor formation in mice have been hampered by the lack of a conditional gene ablation. We examined three mouse models of mammary‐specific ablation of Foxa1 in ductal epithelial cells to identify the best system for complete and mammary‐specific ablation of Foxa1. We found that MMTV‐Cre and MMTV‐rtTA;Tet‐On‐Cre led to partial deletion of Foxa1 and attenuated mammary duct formation, whereas Krt14‐Cre led to complete ablation of Foxa1 and abolished mammary duct formation, in Foxa1 loxP/loxP mice. These results demonstrate that Foxa1 is essential for mammary duct formation, and reveal a series of mouse models in which mammary expression of Foxa1 can be attenuated or completely blocked. Our study also suggests a potentially powerful model for complete ablation of Foxa1 in mammary epithelial cells using Krt14‐driven Cre expression in an inducible manner, such as Krt14‐rtTA;Tet‐On‐Cre . This model system will facilitate further in vivo functional studies of Foxa1 or other factors in mammary gland development and tumor formation and progression. genesis 54:277–285, 2016. © 2016 Wiley Periodicals, Inc.

Abstract As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies. Clin Cancer Res; 22(2); 284–90. ©2016 AACR.

AbstractKernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant‐ and microbiome‐based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method.