A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1+ individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1+ tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3+, CD5+, CD4−, CD8+, CD45Ro+, CD56− immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1+) target cells, PTH-rP+/HLA-A2.1+ CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1+ targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer. © 2001 Cancer Research Campaign http://www.bjcancer.co

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Site-selective cyclic AMP analogs as new biological tools in growth control, differentiation, and proto-oncogene regulation.

The physiologic role of cyclic adenosine monophosphate (cAMP) in the growth control of a spectrum of human cancer lines, including leukemic lines, and v-rasH oncogene-transformed NIH/3T3 cells is demonstrated by the use of site-selective cAMP analogs. These cAMP analogs, which can select either of the two known cAMP binding sites of the cAMP receptor protein, induce potent growth inhibition, phenotypic change, and differentiation (leukemic cells) of cancer cells at micromolar concentrations with no sign of cytotoxicity. The growth inhibition parallels selective modulation of cAMP-dependent protein kinase isozymes, type I versus type II, and suppression of cellular proto-oncogene expression. Site-selective cAMP analogs thus provide new biological tools for investigating cell proliferation and differentiation and also for the improved management of human cancers

The Swift gamma-ray burst mission

The Swift mission, scheduled for launch in 2004, is a multiwavelength observatory for gamma-ray burst (GRB) astronomy. It is a first-of-its-kind autonomous rapid-slewing satellite for transient astronomy and pioneers the way for future rapid-reaction and multiwavelength missions. It will be far more powerful than any previous GRB mission, observing more than 100 bursts yr(-1) and performing detailed X-ray and UV/optical afterglow observations spanning timescales from 1 minute to several days after the burst. The objectives are to (1) determine the origin of GRBs, (2) classify GRBs and search for new types, (3) study the interaction of the ultrarelativistic outflows of GRBs with their surrounding medium, and (4) use GRBs to study the early universe out to z>10. The mission is being developed by a NASA-led international collaboration. It will carry three instruments: a new-generation wide-field gamma-ray (15-150 keV) detector that will detect bursts, calculate 1'-4' positions, and trigger autonomous spacecraft slews; a narrow-field X-ray telescope that will give 5" positions and perform spectroscopy in the 0.2-10 keV band; and a narrow-field UV/optical telescope that will operate in the 170-600 nm band and provide 0".3 positions and optical finding charts. Redshift determinations will be made for most bursts. In addition to the primary GRB science, the mission will perform a hard X-ray survey to a sensitivity of similar to1 mcrab (similar to2x10(-11) ergs cm(-2) s(-1) in the 15-150 keV band), more than an order of magnitude better than HEAO 1 A-4. A flexible data and operations system will allow rapid follow-up observations of all types of high-energy transients, with rapid data downlink and uplink available through the NASA TDRSS system. Swift transient data will be rapidly distributed to the astronomical community, and all interested observers are encouraged to participate in follow-up measurements. A Guest Investigator program for the mission will provide funding for community involvement. Innovations from the Swift program applicable to the future include (1) a large-area gamma-ray detector using the new CdZnTe detectors, (2) an autonomous rapid-slewing spacecraft, (3) a multiwavelength payload combining optical, X-ray, and gamma-ray instruments, (4) an observing program coordinated with other ground-based and space-based observatories, and (5) immediate multiwavelength data flow to the community. The mission is currently funded for 2 yr of operations, and the spacecraft will have a lifetime to orbital decay of similar to8 yr

Defining pediatric traumatic brain injury using International Classification of Diseases Version 10 Codes: A systematic review

Background: Although healthcare administrative data are commonly used for traumatic brain injury (TBI) research, there is currently no consensus or consistency on the International Classification of Diseases Version 10 (ICD-10) codes used to define TBI among children and youth internationally. This study systematically reviewed the literature to explore the range of ICD-10 codes that are used to define TBI in this population. The identification of the range of ICD-10 codes to define this population in administrative data is crucial, as it has implications for policy, resource allocation, planning of healthcare services, and prevention strategies. Methods: The databases MEDLINE, MEDLINE In-Process, Embase, PsychINFO, CINAHL, SPORTDiscus, and Cochrane Database of Systematic Reviews were systematically searched. Grey literature was searched using Grey Matters and Google. Reference lists of included articles were also searched for relevant studies. Two reviewers independently screened all titles and abstracts using pre-defined inclusion and exclusion criteria. A full text screen was conducted on articles that met the first screen inclusion criteria. All full text articles that met the pre-defined inclusion criteria were included for analysis in this systematic review. Results: A total of 1,326 publications were identified through the predetermined search strategy and 32 articles/reports met all eligibility criteria for inclusion in this review. Five articles specifically examined children and youth aged 19 years or under with TBI. ICD-10 case definitions ranged from the broad injuries to the head codes (ICD-10 S00 to S09) to concussion only (S06.0). There was overwhelming consensus on the inclusion of ICD-10 code S06, intracranial injury, while codes S00 (superficial injury of the head), S03 (dislocation, sprain, and strain of joints and ligaments of head), and S05 (injury of eye and orbit) were only used by articles that examined head injury, none of which specifically examined children and youth. Conclusion: This review provides evidence for discussion on how best to use ICD codes for different goals. This is an important first step in reaching an appropriate definition and can inform future work on reaching consensus on the ICD-10 codes to define TBI for this vulnerable population