Grainyhead-like-2 inhibits the co-activator p300, suppressing tubulogenesis and the epithelial-mesenchymal transition

Tumor progression and developmental morphogenesis require transient or stable Epithelial-Mesenchymal transitions (EMT) to modulate epithelial junctional complexes allowing programmed migration, invasion, and anoikis resistance of cells. Grainyhead-like-2 (GRHL2), an epithelial master-regulatory transcription factor, suppresses EMT and causes a mesenchymal-epithelial transition to the default epithelial phenotype. This body of work investigates the role of GRHL2 in kidney cancer, in kidney development using a kidney specific GRHL2 knockout mouse model, and in tubulogenesis using Madin-Darby Canine Kidney (MDCK) cells. In kidney cancer, GRHL2 was not expressed in the normal kidney proximal tubule epithelial cells which are thought to be the progenitors of clear cell renal cell carcinomas. However, GRHL2 could function as biomarker to differentiate renal cell carcinoma subtypes. In kidney development, a large amount of evidence suggests Grhl2 is a critical regulator of this process. However, kidney specific Grhl2 knockout mice did not elucidate the role of Grhl2 in the developing kidney for technical reasons, and this area needs to be further investigated. In the MDCK model, GRHL2 was required for cystogenesis, but it suppressed Hepatocyte Growth Factor-induced tubulogenesis, a process requiring transient, partial EMT. Subsequent results demonstrated that GRHL2 suppressed tubulogenesis by inhibiting the histone acetyltransferase co-activator, p300, thereby preventing the induction of matrix metalloproteases and other p300-dependent genes required for tubulogenesis. A thirteen amino acid region (425-437aa) of GRHL2 was required and sufficient for the inhibition of p300 histone acetyltransferase activity, the suppression of tubulogenesis and the interference with EMT. These results demonstrate that p300 is required for EMT plasticity occurring in tubulogenesis or tumor progression, and that GRHL2 suppresses EMT in both contexts, through inhibition of p300

Local cultures in institutional contexts: The functions of academic departments in liberal arts colleges

The academic department remains understudied as a context of faculty work, particularly in institutional settings beyond the research university. In this article, we report findings from a study of faculty experiences within academic departments in liberal arts colleges, through analysis of interviews with 55 faculty members representing a 13-member consortium of liberal arts institutions in the mid-western U.S. Through inductive analysis and deductive coding from existing models, we identified five functions of departments in liberal arts colleges, including: (a) faculty hiring, retention, and promotion; (b) new faculty socialization; (c) informal interactions, mentoring, and network-building; (d) establishing and communicating institutional and departmental policies, practices, and procedures; and (e) the structuring of academic work. Findings suggest that departmental functions in liberal arts colleges are generally the same as those in other institution types, but play out differently and thus have different consequences for academic careers. Across functions, liberal arts colleges seem to be undergoing an evolution, or perhaps revolution, that has implications for academic work in such contexts

Photoionization of Galactic Halo Gas by Old Supernova Remnants

We present new calculations on the contribution from cooling hot gas to the photoionization of warm ionized gas in the Galaxy. We show that hot gas in cooling supernova remnants (SNRs) is an important source of photoionization, particularly for gas in the halo. We find that in many regions at high latitude this source is adequate to account for the observed ionization so there is no need to find ways to transport stellar photons from the disk. The flux from cooling SNRs sets a floor on the ionization along any line of sight. Our model flux is also shown to be consistent with the diffuse soft X-ray background and with soft X-ray observations of external galaxies. We consider the ionization of the clouds observed towards the halo star HD 93521, for which there are no O stars close to the line of sight. We show that the observed ionization can be explained successfully by our model EUV/soft X-ray flux from cooling hot gas. In particular, we can match the H alpha intensity, the S++/S+ ratio, and the C+* column. From observations of the ratios of columns of C+* and either S+ or H0, we are able to estimate the thermal pressure in the clouds. The slow clouds require high (~10^4 cm^-3 K) thermal pressures to match the N(C+*)/N(S+) ratio. Additional heating sources are required for the slow clouds to maintain their ~7000 K temperatures at these pressures, as found by Reynolds, Hausen & Tufte (1999).Comment: AASTeX 5.01; 34 pages, 2 figures; submitted to Astrophysical Journa

Development of 3-D Ice Accretion Measurement Method

A research plan is currently being implemented by NASA to develop and validate the use of a commercial laser scanner to record and archive fully three-dimensional (3-D) ice shapes from an icing wind tunnel. The plan focused specifically upon measuring ice accreted in the NASA Icing Research Tunnel (IRT). The plan was divided into two phases. The first phase was the identification and selection of the laser scanning system and the post-processing software to purchase and develop further. The second phase was the implementation and validation of the selected system through a series of icing and aerodynamic tests. Phase I of the research plan has been completed. It consisted of evaluating several scanning hardware and software systems against an established selection criteria through demonstrations in the IRT. The results of Phase I showed that all of the scanning systems that were evaluated were equally capable of scanning ice shapes. The factors that differentiated the scanners were ease of use and the ability to operate in a wide range of IRT environmental conditions

Grainyhead-like 2 inhibits the coactivator p300, suppressing tubulogenesis and the epithelial–mesenchymal transition

Developmental morphogenesis and tumor progression require a transient or stable breakdown of epithelial junctional complexes to permit programmed migration, invasion, and anoikis resistance, characteristics endowed by the epithelial–mesenchymal transition (EMT). The epithelial master-regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses and reverses EMT, causing a mesenchymal–epithelial transition to the default epithelial phenotype. Here we investigated the role of GRHL2 in tubulogenesis of Madin–Darby canine kidney cells, a process requiring transient, partial EMT. GRHL2 was required for cystogenesis, but it suppressed tubulogenesis in response to hepatocyte growth factor. Surprisingly, GRHL2 suppressed this process by inhibiting the histone acetyltransferase coactivator p300, preventing the induction of matrix metalloproteases and other p300-dependent genes required for tubulogenesis. A 13–amino acid region of GRHL2 was necessary for inhibition of p300, suppression of tubulogenesis, and interference with EMT. The results demonstrate that p300 is required for partial or complete EMT occurring in tubulogenesis or tumor progression and that GRHL2 suppresses EMT in both contexts through inhibition of p300

17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males

Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17‐α estradiol (17aE2), a less feminizing structural isomer of 17‐β estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these anti‐aging effects extend to anatomical and functional aging—important in late‐life health—and whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in late‐life 17aE2‐treated mice better maintain body weight. In 17aE2‐treated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sex‐specific responses to 17aE2—metabolomic, structural, and functional—are regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an anti‐aging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of late‐life function even when started after middle age.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/1/acel12920_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/2/acel12920.pd

Metabolic targeting, immunotherapy and radiation in locally advanced non-small cell lung cancer: Where do we go from here?

In the US, there are ~250,000 new lung cancer diagnoses and ~130,000 deaths per year, and worldwide there are an estimated 1.6 million deaths per year from this deadly disease. Lung cancer is the most common cause of cancer death worldwide, and it accounts for roughly a quarter of all cancer deaths in the US. Non-small cell lung cancer (NSCLC) represents 80-85% of these cases. Due to an enormous tobacco cessation effort, NSCLC rates in the US are decreasing, and the implementation of lung cancer screening guidelines and other programs have resulted in a higher percentage of patients presenting with potentially curable locoregional disease, instead of distant disease. Exciting developments in molecular targeted therapy and immunotherapy have resulted in dramatic improvement in patients’ survival, in combination with new surgical, pathological, radiographical, and radiation techniques. Concurrent platinum-based doublet chemoradiation therapy followed by immunotherapy has set the benchmark for survival in these patients. However, despite these advances, ~50% of patients diagnosed with locally advanced NSCLC (LA-NSCLC) survive long-term. In patients with local and/or locoregional disease, chemoradiation is a critical component of curative therapy. However, there remains a significant clinical gap in improving the efficacy of this combined therapy, and the development of non-overlapping treatment approaches to improve treatment outcomes is needed. One potential promising avenue of research is targeting cancer metabolism. In this review, we will initially provide a brief general overview of tumor metabolism as it relates to therapeutic targeting. We will then focus on the intersection of metabolism on both oxidative stress and anti-tumor immunity. This will be followed by discussion of both tumor- and patient-specific opportunities for metabolic targeting in NSCLC. We will then conclude with a discussion of additional agents currently in development that may be advantageous to combine with chemo-immuno-radiation in NSCLC

Struggling to a monumental triumph : Re-assessing the final stages of the smallpox eradication program in India, 1960-1980

The global smallpox program is generally presented as the brainchild of a handful of actors from the WHO headquarters in Geneva and at the agency's regional offices. This article attempts to present a more complex description of the drive to eradicate smallpox. Based on the example of India, a major focus of the campaign, it is argued that historians and public health officials should recognize the varying roles played by a much wider range of participants. Highlighting the significance of both Indian and international field officials, the author shows how bureaucrats and politicians at different levels of administration and society managed to strengthen—yet sometimes weaken—important program components. Centrally dictated strategies developed at WHO offices in Geneva and New Delhi, often in association with Indian federal authorities, were reinterpreted by many actors and sometimes changed beyond recognition