Intercellular Friction and Motility Drive Orientational Order in Cell Monolayers

Spatiotemporal patterns in multicellular systems are important to understanding tissue dynamics, for instance, during embryonic development and disease. Here, we use a multiphase field model to study numerically the behavior of a near-confluent monolayer of deformable cells with intercellular friction. Varying friction and cell motility drives a solid-liquid transition, and near the transition boundary, we find the emergence of nematic order of cell deformation driven by shear-aligning cellular flows. Intercellular friction endows the monolayer with a finite viscosity, which significantly increases the spatial correlation in the flow and, concomitantly, the extent of nematic order. We also show that hexatic and nematic order are tightly coupled and propose a mechanical-geometric model for the colocalization of +1/2 nematic defects and 5-7 disclination pairs, which are the structural defects in the hexatic phase. Such topological defects coincide with regions of high cell-cell overlap, suggesting that they may mediate cellular extrusion from the monolayer, as found experimentally. Our results delineate a mechanical basis for the recent observation of nematic and hexatic order in multicellular collectives in experiments and simulations and pinpoint a generic pathway to couple topological and physical effects in these systems

Surgical management of primary colonic lymphoma: Big data for a rare problem

Background and ObjectivesPrimary colonic lymphoma (PCL) is rare, heterogeneous, and presents a therapeutic challenge for surgeons. Optimal treatment strategies are difficult to standardize, leading to variation in therapy. Our objective was to describe the patient characteristics, short‐term outcomes, and five‐year survival of patients undergoing nonpalliative surgery for PCL.MethodsWe performed a retrospective cohort analysis in the National Cancer Database. Included patients underwent surgery for PCL between 2004 to 2014. Patients with metastases and palliative operations were excluded. Univariate predictors of overall survival were analyzed using multivariable Cox proportional hazard analysis.ResultsWe identified 2153 patients. Median patient age was 68. Diffuse large B‐cell lymphoma accounted for 57% of tumors. 30‐ and 90‐Day mortality were high (5.6% and 11.1%, respectively). Thirty‐nine percent of patients received adjuvant chemotherapy. For patients surviving 90 days, 5‐year survival was 71.8%. Chemotherapy improved survival (surgery+chemo, 75.4% vs surgery, 68.6%; P = .01). Adjuvant chemotherapy was associated with overall survival after controlling for age, comorbidity, and lymphoma subtype (HR 1.27; 95% CI, 1.07‐1.51; P = .01).ConclusionsPatients undergoing surgery for PCL have high rates of margin positivity and high short‐term mortality. Chemotherapy improves survival, but <50% receive it. These data suggest the opportunity for improvement of care in patients with PCL.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150597/1/jso25582_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150597/2/jso25582.pd

Metformin and erlotinib synergize to inhibit basal breast cancer

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDAMB- 468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation

Submillimeter Follow-up of WISE-Selected Hyperluminous Galaxies

We have used the Caltech Submillimeter Observatory (CSO) to follow-up a sample of WISE-selected, hyperluminous galaxies, so called W1W2-dropout galaxies. This is a rare (~ 1000 all-sky) population of galaxies at high redshift (peaks at z=2-3), that are faint or undetected by WISE at 3.4 and 4.6 um, yet are clearly detected at 12 and 22 um. The optical spectra of most of these galaxies show significant AGN activity. We observed 14 high-redshift (z > 1.7) W1W2-dropout galaxies with SHARC-II at 350 to 850 um, with 9 detections; and observed 18 with Bolocam at 1.1 mm, with five detections. Warm Spitzer follow-up of 25 targets at 3.6 and 4.5 um, as well as optical spectra of 12 targets are also presented in the paper. Combining WISE data with observations from warm Spitzer and CSO, we constructed their mid-IR to millimeter spectral energy distributions (SEDs). These SEDs have a consistent shape, showing significantly higher mid-IR to submm ratios than other galaxy templates, suggesting a hotter dust temperature. We estimate their dust temperatures to be 60-120 K using a single-temperature model. Their infrared luminosities are well over 10^{13} Lsun. These SEDs are not well fitted with existing galaxy templates, suggesting they are a new population with very high luminosity and hot dust. They are likely among the most luminous galaxies in the Universe. We argue that they are extreme cases of luminous, hot dust-obscured galaxies (DOGs), possibly representing a short evolutionary phase during galaxy merging and evolution. A better understanding of their long-wavelength properties needs ALMA as well as Herschel data.Comment: Will be Published on Sep 1, 2012 by Ap

Regulation of PTEN Inhibition by the Pleckstrin Homology Domain of P-REX2 During Insulin Signaling and Glucose Homeostasis

Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic density-95/Discs large/zona occludens-1-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring diffuse B-cell lymphoma homology domain. Consistent with its function as a PTEN inhibitor, deletion of Prex2 in fibroblasts and mice results in increased Pten activity and decreased insulin signaling in liver and adipose tissue. Prex2 deletion also leads to reduced glucose uptake and insulin resistance. In human adipose tissue, P-REX2 protein expression is decreased and PTEN activity is increased in insulin-resistant human subjects. Taken together, these results indicate a functional role for P-REX2 PH-domain-mediated inhibition of PTEN in regulating insulin sensitivity and glucose homeostasis and suggest that loss of P-REX2 expression may cause insulin resistance

No More Active Galactic Nuclei in Clumpy Disks Than in Smooth Galaxies at z~2 in CANDELS / 3D-HST

We use CANDELS imaging, 3D-HST spectroscopy, and Chandra X-ray data to investigate if active galactic nuclei (AGNs) are preferentially fueled by violent disk instabilities funneling gas into galaxy centers at 1.3<z<2.4. We select galaxies undergoing gravitational instabilities using the number of clumps and degree of patchiness as proxies. The CANDELS visual classification system is used to identify 44 clumpy disk galaxies, along with mass-matched comparison samples of smooth and intermediate morphology galaxies. We note that, despite being being mass-matched and having similar star formation rates, the smoother galaxies tend to be smaller disks with more prominent bulges compared to the clumpy galaxies. The lack of smooth extended disks is probably a general feature of the z~2 galaxy population, and means we cannot directly compare with the clumpy and smooth extended disks observed at lower redshift. We find that z~2 clumpy galaxies have slightly enhanced AGN fractions selected by integrated line ratios (in the mass-excitation method), but the spatially resolved line ratios indicate this is likely due to extended phenomena rather than nuclear AGNs. Meanwhile the X-ray data show that clumpy, smooth, and intermediate galaxies have nearly indistinguishable AGN fractions derived from both individual detections and stacked non-detections. The data demonstrate that AGN fueling modes at z~1.85 - whether violent disk instabilities or secular processes - are as efficient in smooth galaxies as they are in clumpy galaxies.Comment: ApJ accepted. 17 pages, 17 figure