HSF1 as a Cancer Biomarker and Therapeutic Target

Heat shock factor 1 (HSF1) was discovered in 1984 as the master regulator of the heat shock response. In this classical role, HSF1 is activated following cellular stresses such as heat shock that ultimately lead to HSF1-mediated expression of heat shock proteins to protect the proteome and survive these acute stresses. However, it is now becoming clear that HSF1 also plays a significant role in several diseases, perhaps none more prominent than cancer. HSF1 appears to have a pleiotropic role in cancer by supporting multiple facets of malignancy including migration, invasion, proliferation, and cancer cell metabolism among others. Because of these functions, and others, of HSF1, it has been investigated as a biomarker for patient outcomes in multiple cancer types. HSF1 expression alone was predictive for patient outcomes in multiple cancer types but in other instances, markers for HSF1 activity were more predictive. Clearly, further work is needed to tease out which markers are most representative of the tumor promoting effects of HSF1. Additionally, there have been several attempts at developing small molecule inhibitors to reduce HSF1 activity. All of these HSF1 inhibitors are still in preclinical models but have shown varying levels of efficacy at suppressing tumor growth. The growth of research related to HSF1 in cancer has been enormous over the last decade with many new functions of HSF1 discovered along the way. In order for these discoveries to reach clinical impact, further development of HSF1 as a biomarker or therapeutic target needs to be continued

Effects of biceps tension and superior humeral head translation on the glenoid labrum

We sought to understand the effects of superior humeral head translation and load of the long head of biceps on the pathomechanics of the superior glenoid labrum by predicting labral strain. Using micro‐CT cadaver images, a finite element model of the glenohumeral joint was generated, consisting of humerus, glenoid bone, cartilages, labrum, and biceps tendon. A glenohumeral compression of 50 N and biceps tensions of 0, 22, 55, and 88 N were applied. The humeral head was superiorly translated from 0 to 5 mm in 1‐mm increments. The highest labral strain occurred at the interface with the glenoid cartilage and bone beneath the origin of the biceps tendon. The maximum strain was lower than the reported failure strain. The humeral head motion had relatively greater effect than biceps tension on the increasing labral strain. This supports the mechanistic hypothesis that superior labral lesions result mainly from superior migration of the humeral head, but also from biceps tension. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1424–1429, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108670/1/jor22688.pd

Effects of biceps tension on the torn superior glenoid labrum

The purpose of this study was to evaluate the role of the tension on the long head of the biceps tendon in the propagation of SLAP tears by studying the mechanical behavior of the torn superior glenoid labrum. A previously validated finite element model was extended to include a glenoid labrum with type II SLAP tears of three different sizes. The strain distribution within the torn labral tissue with loading applied to the biceps tendon was investigated and compared to the inact and unloaded conditions. The anterior and posterior edges of each SLAP tear experienced the highest strain in the labrum. Labral strain increased with increasing biceps tension. This effect was stronger in the labrum when the size of the tear exceeded the width of the biceps anchor on the superior labrum. Thus, this study indicates that biceps tension influences the propagation of a SLAP tear more than it does the initiation of a tear. Additionally, it also suggests that the tear size greater than the biceps anchor site as a criterion in determining optimal treatment of a type II SLAP tear. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1545–1551, 2015.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113101/1/jor22888.pd

Control of Formation-Flying Multi-Element Space Interferometers with Direct Interferometer-Output Feedback

The long-baseline space interferometer concept involving formation flying of multiple spacecrafts holds great promise as future space missions for high-resolution imagery. A major challenge of obtaining high-quality interferometric synthesized images from long-baseline space interferometers is to accurately control these spacecraft and their optics payloads in the specified configuration. Our research focuses on the determination of the optical errors to achieve fine control of long-baseline space interferometers without resorting to additional sensing equipment. We present a suite of estimation tools that can effectively extract from the raw interferometric image relative x/y, piston translational and tip/tilt deviations at the exit pupil aperture. The use of these error estimates in achieving control of the interferometer elements is demonstrated using simulated as well as laboratory-collected interferometric stellar images

Longitudinal, Diet-induced Weight Gain is Associated with Increased Blood Monocytes and Reduced TLR4 Expression

Excessive weight gain increases systemic inflammation resulting in increased disease risk. Toll-like receptor 4 (TLR4) reportedly mediates increases in inflammation; however, its role has not been fully evaluated. Objective. The purpose of this study was to determine the longitudinal effect of diet-induced weight gain on blood monocyte concentration and cell-surface TLR4 expression. Research Methods & Procedures. Male CD-1 mice were randomly assigned to high-fat (HF, n = 12) or low-fat (LF, n = 13) groups. Non-lethal, saphenous vein blood samples were collected at 0, 4, 8 and 12 weeks of treatment. Three-color flow cytometry was used to measure monocyte (CD11b+/CD14+) concentration and TLR4 cells-surface expression. Data were analyzed with a repeated measures ANOVA; significance was set at P\u3c0.05. Results. Body weight at week 12 was 21% greater in HF than LF (P\u3c0.05). At week 12 HF had 155% more monocytes (P\u3c0.05) with 24% less TLR4; Monocyte concentration and body weight at week 12 was negatively correlated with TLR4 gMFI (P\u3c0.05). Conclusions. The observed effects of high-fat feeding on blood monocytes are consistent with a phenotype, which may be associated with premature morbidity. The observed monocyte responses may be associated with immune dysfunction and diminished response to infection

Control of Formation-Flying Multi-Element Space Interferometers with Direct Interferometer-Output Feedback

The long-baseline space interferometer concept involving formation flying of multiple spacecraft holds great promise as future space missions for high-resolution imagery. A major challenge of obtaining high-quality interferometric synthesized images from long-baseline space interferometers is to accurately control these spacecraft and their optics payloads in the specified configuration. Our research focuses on the determination of the optical errors to achieve fine control of long-baseline space interferometers without resorting to additional sensing equipment. We present a suite of estimation tools that can effectively extract from the raw interferometric image relative x/y, piston translational and tip/tilt deviations at the exit pupil aperture. The use of these error estimates in achieving control of the interferometer elements is demonstrated using simulated as well as laboratory-collected interferometric stellar images

Access to AgriculturalInputs, Technology and Information, Communicating with Farmers,and the Role of Women in Agriculture: Perceptions of Iraqi Extension Agents

The goal of this study was to gain a more comprehensive understanding ofaccess to inputs,technology and information available toIraqi extension agents,and to ascertain current farmercommunication strategies and gender roles within the diverse Iraq agricultural extension system.The conflicts, government policies, and economic sanctions that have enveloped Iraq over thelast several decades have significantly impacted access to agricultural resources. Iraqi extensionpersonnel participating inthe Iraq AgriculturalExtension Revitalization (IAER)programprovided their perspective on the availability of agricultural supplies, technology and relatedinformation. About two-thirds of the extension agents indicated that the flow and availability ofagricultural supplies has become less restricted and generally felt that there was greater accessto basic agricultural information compared to the previous decade. Despite perceivingnoticeable improvement overall in access to agricultural supplies and technology, over 83% ofthe program attendees agreed that access to agricultural inputs was currently insufficient tosuccessfully promote productive agricultural practices. An overwhelming preference for face-to-face communication by both farmers and extension personnel also limits the extent to whichagricultural information can be disseminated. In addition, several regional and gender-baseddifferences emerged.Notably, it appears that farmers donot approachfemaleextensionpersonnel equally, wherein better educated farmers are more likely to interact with femaleextensionagents.We suggest that an approach based on a horizontal exchange of knowledgebetween extension personnel and local farmers, coupled with a better integration of womenextension personnel, will help a revitalized Iraqi extension system achieve greater agriculturalsustainabilit

High Mass Triple Systems: The Classical Cepheid Y Car

We have obtained an HST STIS ultraviolet high dispersion Echelle mode spectrum the binary companion of the double mode classical Cepheid Y Car. The velocity measured for the hot companion from this spectrum is very different from reasonable predictions for binary motion, implying that the companion is itself a short period binary. The measured velocity changed by 7 km/ s during the 4 days between two segments of the observation confirming this interpretation. We summarize "binary" Cepheids which are in fact members of triple system and find at least 44% are triples. The summary of information on Cepheids with orbits makes it likely that the fraction is under-estimated.Comment: accepted by A

A Resolved Ring of Debris Dust around the Solar Analog HD 107146

We present resolved images of the dust continuum emission from the debris disk around the young (80-200 Myr) solar-type star HD 107146 with CARMA at λ = 1.3 mm and the CSO at λ = 350 μ. Both images show that the dust emission extends over an approximately 10" diameter region. The high-resolution (3") CARMA image further reveals that the dust is distributed in a partial ring with significant decrease in a flux inward of 97 AU. Two prominent emission peaks appear within the ring separated by ~140° in the position angle. The morphology of the dust emission is suggestive of dust captured into a mean motion resonance, which would imply the presence of a planet at an orbital radius of ~45-75 AU

TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment

Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment