Lymphoscintigraphy and triangulated body marking for morbidity reduction during sentinel node biopsy in breast cancer

Current trends in patient care include the desire for minimizing invasiveness of procedures and interventions. This aim is reflected in the increasing utilization of sentinel lymph node biopsy, which results in a lower level of morbidity in breast cancer staging, in comparison to extensive conventional axillary dissection. Optimized lymphoscintigraphy with triangulated body marking is a clinical option that can further reduce morbidity, more than when a hand held gamma probe alone is utilized. Unfortunately it is often either overlooked or not fully understood, and thus not utilized. This results in the unnecessary loss of an opportunity to further reduce morbidity. Optimized lymphoscintigraphy and triangulated body marking provides a detailed 3 dimensional map of the number and location of the sentinel nodes, available before the first incision is made. The number, location, relevance based on time/sequence of appearance of the nodes, all can influence 1) where the incision is made, 2) how extensive the dissection is, and 3) how many nodes are removed. In addition, complex patterns can arise from injections. These include prominent lymphatic channels, pseudo-sentinel nodes, echelon and reverse echelon nodes and even contamination, which are much more difficult to access with the probe only. With the detailed information provided by optimized lymphoscintigraphy and triangulated body marking, the surgeon can approach the axilla in a more enlightened fashion, in contrast to when the less informed probe only method is used. This allows for better planning, resulting in the best cosmetic effect and less trauma to the tissues, further reducing morbidity while maintaining adequate sampling of the sentinel node(s)

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Enhanced Expansion and Sustained Inductive Function of Skin-Derived Precursor Cells in Computer-Controlled Stirred Suspension Bioreactors

Endogenous dermal stem cells (DSCs) reside in the adult hair follicle mesenchyme and can be isolated and grown in vitro as self-renewing colonies called skin-derived precursors (SKPs). Following transplantation into skin, SKPs can generate new dermis and reconstitute the dermal papilla and connective tissue sheath, suggesting they could have important therapeutic value for the treatment of skin disease (alopecia) or injury. Controlled cell culture processes must be developed to efficiently and safely generate sufficient stem cell numbers for clinical use. Compared with static culture, stirred-suspension bioreactors generated fivefold greater expansion of viable SKPs. SKPs from each condition were able to repopulate the dermal stem cell niche within established hair follicles. Both conditions were also capable of inducing de novo hair follicle formation and exhibited bipotency, reconstituting the dermal papilla and connective tissue sheath, although the efficiency was significantly reduced in bioreactor-expanded SKPs compared with static conditions. We conclude that automated bioreactor processing could be used to efficiently generate large numbers of autologous DSCs while maintaining their inherent regenerative function

Long-Range Exciton Diffusion in Two-Dimensional Assemblies of Cesium Lead Bromide Perovskite Nanocrystals

F\"orster Resonant Energy Transfer (FRET)-mediated exciton diffusion through artificial nanoscale building block assemblies could be used as a new optoelectronic design element to transport energy. However, so far nanocrystal (NC) systems supported only diffusion length of 30 nm, which are too small to be useful in devices. Here, we demonstrate a FRET-mediated exciton diffusion length of 200 nm with 0.5 cm2/s diffusivity through an ordered, two-dimensional assembly of cesium lead bromide perovskite nanocrystals (PNC). Exciton diffusion was directly measured via steady-state and time-resolved photoluminescence (PL) microscopy, with physical modeling providing deeper insight into the transport process. This exceptionally efficient exciton transport is facilitated by PNCs high PL quantum yield, large absorption cross-section, and high polarizability, together with minimal energetic and geometric disorder of the assembly. This FRET-mediated exciton diffusion length matches perovskites optical absorption depth, opening the possibility to design new optoelectronic device architectures with improved performances, and providing insight into the high conversion efficiencies of PNC-based optoelectronic devices

Constraining Dust and Molecular Gas Properties in Lyα Blobs at z ~ 3

In order to constrain the bolometric luminosities, dust properties, and molecular gas content of giant Lyα nebulae, the so-called Lyα blobs, we have carried out a study of dust continuum and CO line emission in two well-studied representatives of this population at z ~ 3: an Lyα blob discovered by its strong Spitzer Multiband Infrared Photometer 24 μm detection (LABd05) and the Steidel blob 1 (SSA22-LAB01). We find that the spectral energy distribution of LABd05 is well described by an active-galactic-nucleus-starburst composite template with L_(FIR) = (4.0 ± 0.5) × 10^(12) L_☉, comparable to high-z submillimeter galaxies and ultraluminous infrared galaxies. New Large APEX Bolometer Camera 870 μm measurements rule out the reported Submillimeter Common-User Bolometer Array detection of the SSA22-LAB01 (S_(850 μm) = 16.8 mJy) at the >4σ level. Consistent with this, ultradeep Plateau de Bure Interferometer observations with ~2'' spatial resolution also fail to detect any 1.2 mm continuum source down to ≈0.45 mJy beam^(–1) (3σ). Combined with the existing (sub)millimeter observations in the literature, we conclude that the FIR luminosity of SSA22-LAB01 remains uncertain. No CO line is detected in either case down to integrated flux limits of S_νΔV ≾ 0.25-1.0 Jy km s^(–1), indicating a modest molecular gas reservoir, M(H_2) < (1-3) × 10^(10) M_☉. The non-detections exclude, with high significance (12σ), the previous tentative detection of a CO J = 4-3 line in the SSA22-LAB01. The increased sensitivity afforded by the Atacama Large Millimeter/submillimeter Array will be critical in studying molecular gas and dust in these interesting systems

A New Population of High-z, Dusty Lyα Emitters and Blobs Discovered by WISE: Feedback Caught in the Act?

By combining data from the NASA Wide-field Infrared Survey Explorer (WISE) mission with optical spectroscopy from the W. M. Keck telescope, we discover a mid-IR color criterion that yields a 78% success rate in identifying rare, typically radio-quiet, 1.6 ≾ z ≾ 4.6 dusty Lyα emitters (LAEs). Of these, at least 37% have emission extended on scales of 30-100 kpc and are considered Lyα "blobs" (LABs). The objects have a surface density of only ~0.1 deg^(–2), making them rare enough that they have been largely missed in deep, small area surveys. We measured spectroscopic redshifts for 92 of these galaxies, and find that the LAEs (LABs) have a median redshift of 2.3 (2.5). The WISE photometry coupled with data from Herschel (Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA) reveals that these galaxies are in the Hyper Luminous IR galaxy regime (L IR ≳ 10^(13)-10^(14) L_☉) and have warm colors. They are typically more luminous and warmer than other dusty, z ~ 2 populations such as submillimeter-selected galaxies and dust-obscured galaxies. These traits are commonly associated with the dust being illuminated by intense active galactic nucleus activity. We hypothesize that the combination of spatially extended Lyα, large amounts of warm IR-luminous dust, and rarity (implying a short-lived phase) can be explained if the galaxies are undergoing brief, intense "feedback" transforming them from an extreme dusty starburst/QSO into a mature galaxy

Environment of MAMBO galaxies in the COSMOS field

Submillimeter galaxies (SMG) represent a dust-obscured high-redshift population undergoing massive star formation activity. Their properties and space density have suggested that they may evolve into spheroidal galaxies residing in galaxy clusters. In this paper, we report the discovery of compact (~10"-20") galaxy overdensities centered at the position of three SMGs detected with the Max-Planck Millimeter Bolometer camera (MAMBO) in the COSMOS field. These associations are statistically significant. The photometric redshifts of galaxies in these structures are consistent with their associated SMGs; all of them are between z=1.4-2.5, implying projected physical sizes of ~170 kpc for the overdensities. Our results suggest that about 30% of the radio-identified bright SMGs in that redshift range form in galaxy density peaks in the crucial epoch when most stars formed.Comment: Accepted for publication in ApJ Letter

Regulation of WNT Signaling by VSX2 During Optic Vesicle Patterning in Human Induced Pluripotent Stem Cells

Few gene targets of Visual System Homeobox 2 (VSX2) have been identified despite its broad and critical role in the maintenance of neural retina (NR) fate during early retinogenesis. We performed VSX2 ChIP-seq and ChIP-PCR assays on early stage optic vesicle-like structures (OVs) derived from human iPS cells (hiPSCs), which highlighted WNT pathway genes as direct regulatory targets of VSX2. Examination of early NR patterning in hiPSC-OVs from a patient with a functional null mutation in VSX2 revealed mis-expression and upregulation of WNT pathway components and retinal pigmented epithelium (RPE) markers in comparison to control hiPSCOVs. Furthermore, pharmacological inhibition of WNT signaling rescued the early mutant phenotype, whereas augmentation of WNT signaling in control hiPSC-OVs phenocopied the mutant. These findings reveal an important role for VSX2 as a regulator of WNT signaling and suggest that VSX2 may act to maintain NR identity at the expense of RPE in part by direct repression of WNT pathway constituents