Towards targeting prolactin signaling in human diseases: Stimulate or inhibit?

Prolactin is an anterior pituitary hormone that was originally named for its indispensable role in lactation, but increasingly it is being recognized for pleiotropic roles in metabolism, immune function, pregnancy adaptations and parental behaviour. Prolactin secretion is tightly controlled by a short-loop feedback system whereby prolactin stimulates specific neurons in the hypothalamus to release dopamine, which then inhibits prolactin secretion. During pregnancy and lactation, however, this feedback systems adapts to allow prolonged elevations in prolactin secretion, enabling a range of functions specific to these conditions. Prolactin is also released under conditions of stress in both sexes. Prolactin signals exclusively through the prolactin receptor (Prlr), but this is not a simple system. In target cells, prolactin/Prlr engages various signal transduction mechanisms including JAK2/STAT5 (canonical), PI3K/Akt, MAPK and Src family kinases. There is also evidence of local production of prolactin in non-pituitary tissues, leading to autocrine/paracrine receptor triggering independent of circulating hormone. Adding to this complexity, in many species, including humans, there are multiple ligands for the Prlr. These include placental lactogens that supplement prolactin function in pregnancy, and in primates only, pituitary growth hormone. Moreover, specific proteolytic products of these hormones exert important biological actions independent of Prlr. These functions, that are often completely distinct from those of prolactin, have led to the classification of these fragments as a new class of hormones known as vasoinhibins.Fil: Goffin, Vincent. Universite de Paris V; Francia. Inserm; FranciaFil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Popovic, Vera. University of Belgrade; SerbiaFil: Grattan, David R.. University of Otago; Nueva Zeland

Structure of the full-length TRPV2 channel by cryo-EM.

Transient receptor potential (TRP) proteins form a superfamily Ca(2+)-permeable cation channels regulated by a range of chemical and physical stimuli. Structural analysis of a 'minimal' TRP vanilloid subtype 1 (TRPV1) elucidated a mechanism of channel activation by agonists through changes in its outer pore region. Though homologous to TRPV1, other TRPV channels (TRPV2-6) are insensitive to TRPV1 activators including heat and vanilloids. To further understand the structural basis of TRPV channel function, we determined the structure of full-length TRPV2 at ∼5 Å resolution by cryo-electron microscopy. Like TRPV1, TRPV2 contains two constrictions, one each in the pore-forming upper and lower gates. The agonist-free full-length TRPV2 has wider upper and lower gates compared with closed and agonist-activated TRPV1. We propose these newly revealed TRPV2 structural features contribute to diversity of TRPV channels

Comparison of Post-injection Site Pain Between Technetium Sulfur Colloid and Technetium Tilmanocept in Breast Cancer Patients Undergoing Sentinel Lymph Node Biopsy.

BackgroundNo prior studies have examined injection pain associated with Technetium-99m Tilmanocept (TcTM).MethodsThis was a randomized, double-blinded study comparing postinjection site pain between filtered Technetium Sulfur Colloid (fTcSC) and TcTM in breast cancer lymphoscintigraphy. Pain was evaluated with a visual analogue scale (VAS) (0-100 mm) and the short-form McGill Pain Questionnaire (SF-MPQ). The primary endpoint was mean difference in VAS scores at 1-min postinjection between fTcSC and TcTM. Secondary endpoints included a comparison of SF-MPQ scores between the groups at 5 min postinjection and construction of a linear mixed effects model to evaluate the changes in pain during the 5-min postinjection period.ResultsFifty-two patients underwent injection (27-fTcSC, 25-TcTM). At 1-min postinjection, patients who received fTcSC experienced a mean change in pain of 16.8 mm (standard deviation (SD) 19.5) compared with 0.2 mm (SD 7.3) in TcTM (p = 0.0002). At 5 min postinjection, the mean total score on the SF-MPQ was 2.8 (SD 3.0) for fTcSC versus 2.1 (SD 2.5) for TcTM (p = 0.36). In the mixed effects model, injection agent (p < 0.001), time (p < 0.001) and their interaction (p < 0.001) were associated with change in pain during the 5-min postinjection period. The model found fTcSC resulted in significantly more pain of 15.2 mm (p < 0.001), 11.3 mm (p = 0.001), and 7.5 mm (p = 0.013) at 1, 2, and 3 min postinjection, respectively.ConclusionsInjection with fTcSC causes significantly more pain during the first 3 min postinjection compared with TcTM in women undergoing lymphoscintigraphy for breast cancer

HST astrometry in the Orion Nebula Cluster: census of low-mass runaways

We present a catalog of high-precision proper motions in the Orion Nebula Cluster (ONC), based on Treasury Program observations with the Hubble Space Telescope's (HST) ACS/WFC camera. Our catalog contains 2,454 objects in the magnitude range of $14.2<m_{\rm F775W}<24.7$, thus probing the stellar masses of the ONC from $\sim$0.4 $M_\odot$ down to $\sim$0.02 $M_\odot$ over an area of $\sim$550 arcmin$^2$. We provide a number of internal velocity dispersion estimates for the ONC that indicate a weak dependence on the stellar location and mass. There is good agreement with the published velocity dispersion estimates, although nearly all of them (including ours at $\sigma_{v,x}=0.94$ and $\sigma_{v,y}=1.25$ mas yr$^{-1}$) might be biased by the overlapping young stellar populations of Orion A. We identified 4 new ONC candidate runaways based on HST and the Gaia DR2 data, all with masses less than $\sim$1 $M_\odot$. The total census of known candidate runaway sources is 10 -- one of the largest samples ever found in any Milky Way open star cluster. Surprisingly, none of them has the tangential velocity exceeding 20 km s$^{-1}$. If most of them indeed originated in the ONC, it may compel re-examination of dynamical processes in very young star clusters. It appears that the mass function of the ONC is not significantly affected by the lost runaways.Comment: 16 pages, 10 figures, 5 tables. Accepted for publication in A

Magnetic light

In this paper we report on the observation of novel and highly unusual magnetic state of light. It appears that in small holes light quanta behave as small magnets so that light propagation through such holes may be affected by magnetic field. When arrays of such holes are made, magnetic light of the individual holes forms novel and highly unusual two-dimensional magnetic light material. Magnetic light may soon become a great new tool for quantum communication and computing.Comment: Submitted to Phys.Rev.Lett., 3 figure

Small-x QCD studies with CMS at the LHC

The capabilities of the CMS experiment to study the low-x parton structure and QCD evolution in the proton and the nucleus at LHC energies are presented through four different measurements, to be carried out in Pb-Pb at sqrt(s_NN) = 5.5 TeV: (i) the charged hadron rapidity density $dN_{ch}/d\eta$ and (ii) the ultraperipheral (photo)production of Upsilon; and in p-p at sqrt(s) = 14 TeV: (iii) inclusive forward jets and (iv) Mueller-Navelet dijets (separated by $Delta\eta\gtrsim$ 8).Comment: Quark Matter'06 Proceedings. To appear in J.Phys.

Fast 18F Labeling of a Near-Infrared Fluorophore Enables Positron Emission Tomography and Optical Imaging of Sentinel Lymph Nodes

We combine a novel boronate trap for F− with a near-infrared fluorophore into a single molecule. Attachment to targeting ligands enables localization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). Our first application of this generic tag is to label Lymphoseek (tilmanocept), an agent designed for receptor-specific sentinel lymph node (SLN) mapping. The new conjugate incorporates 18F− in a single, aqueous step, targets mouse SLN rapidly (1 h) with reduced distal lymph node accumulation, permits PET or scintigraphic imaging of SLN, and enables NIRF-guided excision and histological verification even after 18F decay. This embodiment is superior to current SLN mapping agents such as nontargeted [99mTc]sulfur colloids and Isosulfan Blue, as well as the phase III targeted ligand [99mTc]SPECT Lymphoseek counterpart, species that are visible by SPECT or visible absorbance separately. Facile incorporation of 18F into a NIRF probe should promote many synergistic PET and NIRF combinations

Role of Sentinel Lymph Node Biopsy for Oral Squamous Cell Carcinoma: Current Evidence and Future Challenges

Sentinel lymph node biopsy (SLNB) has been used across oncological specialties for prognostication, staging, and identification of occult nodal metastasis. Recent studies demonstrated the potential clinical utility of SLNB in oral cavity squamous cell carcinoma (OCSCC). Elective neck dissection is the current standard of care in early management of OCSCC with depth of invasion greater than 2-4 mm; however, majority of patients ultimately do not have nodal disease on final pathology. SLNB is an alternative procedure widely adopted in early cancer management in many oncological subspecialities. Several considerations such as depth of invasion, nodal mapping, histopathology methods, operator variability, postoperative complications, and advancement in preoperative and intraoperative imaging technology can guide the appropriate application to SLNB in OCSCC. The aim of this review is to discuss the current evidence for SLNB in the treatment of early stage OCSCC, imaging technologies that support SLNB procedures, and studies that are currently underway