Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study ...of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 μg, 3 times daily, increased to 200 μg three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 μg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk.
The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7–141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12–73), and for macroadenomas it was 43% (range, 6–92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study.
Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 μg/liter).
A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the molecules that mediate thermoreception ...by these neurons. Vanilloid Receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here we describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temperature-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temperatures and by a cooling agent, menthol. Our identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.
Abstract Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be ...painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165 a and VEGF-A165 b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165 a is upregulated and predominates over the VEGF-A165 b isoform. We show here that in rats and mice VEGF-A165 a and VEGF-A165 b have opposing effects on pain, and that blocking the proximal splicing event – leading to the preferential expression of VEGF-A165 b over VEGF165 a – prevents pain in vivo. VEGF-A165 a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165 b blocks the effect of VEGF-A165 a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxx a compared to VEGF-Axxx b, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxx a expression and reversed associated neuropathic pain. Exogenous VEGF-A165 b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxx a/VEGF-Axxx b balance by targeting alternative RNA splicing may be a new analgesic strategy.
The search for highly ionizing particles in nuclear track detectors (NTDs) traditionally requires experts to manually search through samples in order to identify regions of interest that could be a ...hint of physics beyond the standard model of particle physics. The advent of automated image acquisition andmodern data science, including machine learningbased processing of data presents an opportunity to accelerate the process of searching for anomalies in NTDs that could be a hint of a new physics avatar. The potential for modern data science applied to this topic in the context of the MoEDAL experiment at the large Hadron collider at the European Centre for Nuclear Research, CERN, is discussed.
This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals ...during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (
Prf1) transcription, and repressed re-expression of memory CTL markers
Bcl6 and IL-7Rα. Binding of Eomes and STAT5 to
Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the
Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Rα and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Rα repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Rα-deficient effector CD8
+ T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1
+ and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development.
► Strong, sustained IL-2 signals promote effector and repress memory CTL development ► IL-2Rα is required for effective effector CTL differentiation during viral infection ► IL-2 induces eomesodermin and perforin gene transcription by recruiting RNA Pol II ► Complex interplay between inflammation and IL-2 for gene regulation in CD8
+ T cells
A Heat-Sensitive TRP Channel Expressed in Keratinocytes Peier, Andrea M.; Reeve, Alison J.; Andersson, David A. ...
Science (American Association for the Advancement of Science),
06/2002, Volume:
296, Issue:
5575
Journal Article
Peer reviewed
Mechanical and thermal cues stimulate a specialized group of sensory neurons that terminate in the skin. Three members of the transient receptor potential (TRP) family of channels are expressed in ...subsets of these neurons and are activated at distinct physiological temperatures. Here, we describe the cloning and characterization of a novel thermosensitive TRP channel. TRPV3 has a unique threshold: It is activated at innocuous (warm) temperatures and shows an increased response at noxious temperatures. TRPV3 is specifically expressed in keratinocytes; hence, skin cells are capable of detecting heat via molecules similar to those in heat-sensing neurons.
An established rift in the Larsen C Ice Shelf, formerly constrained by a suture zone containing marine ice, grew rapidly during 2014 and is likely in the near future to generate the largest calving ...event since the 1980s and result in a new minimum area for the ice shelf. Here we investigate the recent development of the rift, quantify the projected calving event and, using a numerical model, assess its likely impact on ice shelf stability. We find that the ice front is at risk of becoming unstable when the anticipated calving event occurs.
Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism
. By electromagnetic duality, a sufficiently strong magnetic ...field would similarly produce magnetic monopoles, if they exist
. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model
but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size
and strong coupling to photons
. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb-Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe
. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 10
, of Pb-Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.
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