Rapid quasi-periodic oscillations in the relativistic jet of BL Lacertae.

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1-3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image.

The cosmic ray shadow of the Moon observed with the ANTARES neutrino telescope.

One of the main objectives of the ANTARES telescope is the search for point-like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliable way to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i.e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, the Moon shadow is observed with 3.5 σ statistical significance. The detector angular resolution for downward-going muons is 0 . 73 ∘ ± 0 . 14 ∘ . The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.

An algorithm for the reconstruction of high-energy neutrino-induced particle showers and its application to the ANTARES neutrino telescope.

A novel algorithm to reconstruct neutrino-induced particle showers within the ANTARES neutrino telescope is presented. The method achieves a median angular resolution of [Formula: see text] for shower energies below 100 TeV. Applying this algorithm to 6 years of data taken with the ANTARES detector, 8 events with reconstructed shower energies above 10 TeV are observed. This is consistent with the expectation of about 5 events from atmospheric backgrounds, but also compatible with diffuse astrophysical flux measurements by the IceCube collaboration, from which 2-4 additional events are expected. A [Formula: see text] C.L. upper limit on the diffuse astrophysical neutrino flux with a value per neutrino flavour of [Formula: see text] is set, applicable to the energy range from 23 TeV to 7.8 PeV, assuming an unbroken [Formula: see text] spectrum and neutrino flavour equipartition at Earth.

Sperm whale long-range echolocation sounds revealed by ANTARES, a deep-sea neutrino telescope.

Despite dedicated research has been carried out to adequately map the distribution of the sperm whale in the Mediterranean Sea, unlike other regions of the world, the species population status is still presently uncertain. The analysis of two years of continuous acoustic data provided by the ANTARES neutrino telescope revealed the year-round presence of sperm whales in the Ligurian Sea, probably associated with the availability of cephalopods in the region. The presence of the Ligurian Sea sperm whales was demonstrated through the real-time analysis of audio data streamed from a cabled-to-shore deep-sea observatory that allowed the hourly tracking of their long-range echolocation behaviour on the Internet. Interestingly, the same acoustic analysis indicated that the occurrence of surface shipping noise would apparently not condition the foraging behaviour of the sperm whale in the area, since shipping noise was almost always present when sperm whales were acoustically detected. The continuous presence of the sperm whale in the region confirms the ecological value of the Ligurian sea and the importance of ANTARES to help monitoring its ecosystems.

Observation of pulsed gamma-rays above 25 GeV from the Crab pulsar with MAGIC.

One fundamental question about pulsars concerns the mechanism of their pulsed electromagnetic emission. Measuring the high-end region of a pulsar's spectrum would shed light on this question. By developing a new electronic trigger, we lowered the threshold of the Major Atmospheric gamma-ray Imaging Cherenkov (MAGIC) telescope to 25 giga-electron volts. In this configuration, we detected pulsed gamma-rays from the Crab pulsar that were greater than 25 giga-electron volts, revealing a relatively high cutoff energy in the phase-averaged spectrum. This indicates that the emission occurs far out in the magnetosphere, hence excluding the polar-cap scenario as a possible explanation of our measurement. The high cutoff energy also challenges the slot-gap scenario.

Does the distance to normal renal parenchyma (DTNRP) in nephron-sparing surgery for renal cell carcinoma have an effect on survival?

BACKGROUND: The effect of the distance to normal renal parenchyma (DTNRP) on survival after nephron-sparing surgery (NSS) for renal cell cancer (RCC) was analyzed. Additionally, the role of T-classification, tumor diameter and tumor grading was considered. PATIENTS AND METHODS: NSS was performed on 126 patients with RCC between 1988 and 2000. Eighty-six patients were submitted to annual follow-up. These 86 patients were sub-classified into statistical groups according to the distance to normal renal parenchyma (< or = 2mm; > 2mm - < or = 5mm; >5 mm), T-classification, tumor diameter (< or = 20mm; > 20mm - < or = 30 mm; >30 mm - < or = 50mm; > 50mm) and tumor grading. The effect of belonging to one of these groups on survival was analyzed using the Log-Rank-Test (SPSS; version 11.0) and the Kaplan and Meier survival data. The level of significance was set at p < 0.05. RESULTS: During the follow-up period, 4 patients died related to RCC and 15 patients died from other causes. The tumor-specific survival was 95.4%. At the end of 2002, the mean follow-up time was 5.5 years (range 0.1 - 14.7). None of the variables which had been analyzed in our statistical groups had an effect on the overall survival. CONCLUSION: The distance to normal renal parenchyma does not influence survival, suggesting an additional resection to be unnecessary even in cases where the DTNRP is reported by frozen section to be less than 2 mm. RCC up to 5 cn in tumor diameter can be safely removed by NSS, even in the presence of a functional intact contralateral kidney.

[Regional networking of medical and vocational rehabilitation-- the bad Krozingen model]. / Regionale Vernetzung medizinischer und beruflicher Rehabilitation: Das Bad Krozinger Modell.

Regional networking facilitates flexible and individual integration of vocational programmes in medical rehabilitation. We present a pilot project of Theresienklinik II in cooperation with the Education centre for occupation and health (Bildungszentrum Beruf und Gesundheit) in Bad Krozingen. Orthopaedic and cardiac patients who are in danger to lose their capacity to work, participate in an integrated vocational reorientation programme during extended medical rehabilitation. The aim of the pilot project is an early assessment of motivation, work hardening, aptitude and interest, in order to accelerate vocational retraining and reintegration. Within one year 30 patients participated in the programme. Presented are the contents and course of the pilot project. First results show a high patient satisfaction with the programme.

Epidermal growth factor receptor and g250: useful target antigens for antibody mediated cellular cytotoxicity against renal cell carcinoma?

PURPOSE: Monoclonal antibodies are a novel treatment option for certain tumor patients. We evaluated the potential of antibody derivatives against epidermal growth factor receptor and G250, which are 2 candidate antigens on renal cell carcinoma, to recruit effector cells for killing renal cell carcinoma. MATERIAL AND METHODS: As a measure of cytotoxicity, 51chromium release assays against renal cell carcinoma lines were performed using unseparated blood or isolated cell populations as the source of effectors. Blood was obtained from healthy donors, or from patients receiving granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor for enhancing effector cell function. Parental human IgG1 antibodies against epidermal growth factor receptor and G250 were compared with respective chemically linked bispecific antibodies targeting IgA Fc receptor FcalphaRI (CD89), a novel cytotoxic trigger molecule on polymorphonuclear cells and monocytes/macrophages, which were constructed by chemically crosslinking appropriate F(ab') fragments. RESULTS: Renal cell carcinoma lines were highly resistant to complement dependent lysis. With mononuclear effector cells high levels of renal cell carcinoma killing were observed with a humanized epidermal growth factor receptor directed monoclonal antibody, while the same antibody did not recruit granulocytes (polymorphonuclear cells) for antibody dependent cell mediated cytotoxicity. However, polymorphonuclear cells effectively lysed renal cell carcinoma with [FcalphaRI x epidermal growth factor receptor] bispecific antibody. FcalphaRI mediated killing was significantly enhanced when the blood of patients on granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor therapy was analyzed. However, G250 mediated only low levels of killing with mononuclear cell but not with polymorphonuclear effector cells. CONCLUSIONS: Targeting epidermal growth factor receptor proved to recruit efficiently mononuclear or polymorphonuclear cell mediated killing mechanisms, while G250 directed antibody constructs were significantly less effective. Particularly effective renal cell carcinoma killing was observed with combined [FcalphaRI x epidermal growth factor receptor] bispecific antibody and granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor.

Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies.

Studies with gene-modified mice have recently reinforced the importance of Fc receptor-mediated effector mechanisms for the therapeutic efficacy of rituxan and herceptin - two clinically approved antibodies for the treatment of tumor patients. We investigated Fc receptor-dependent tumor cell killing by mononuclear and granulocytic effector cells - comparing human IgG1 antibodies against CD20 or HER-2/neu with their respective FcgammaRI (CD64)-, FcgammaRIII (CD16)-, or FcalphaRI (CD89)-directed bispecific derivatives. With blood from healthy donors as effector source, human IgG1 and FcgammaRIII (CD16)-directed bispecific antibodies proved most effective in recruiting mononuclear effector cells, whereas tumor cell killing by granulocytes was most potently triggered by FcalphaRI-directed bispecific constructs. Granulocyte-mediated tumor cell lysis was significantly enhanced when blood from G-CSF- or GM-CSF-treated patients was investigated. Interestingly, however, both myeloid growth factors improved effector cell recruitment by different mechanisms, which were furthermore dependent on the tumor target antigen, and on the selected cytotoxic Fc receptor.

Flow cytometric analysis of DNA-aneuploidy subgroups and proliferation in renal cell carcinoma.

BACKGROUND: The course of patients suffering from renal cell carcinoma varies considerably and cannot be predicted by tumor stage and grade alone. However, it is crucial to select patients with high risk of progression and to commence adjuvant immuno-chemotherapy in good time. MATERIALS AND METHODS: Multiple samples of 71 kidney tumors were studied by DNA flow cytometry. Aneuploidy was classified into subgroups employing the DNA-index. In tumors of euploid pattern and corresponding normal tissue cell cycle analysis was performed. RESULTS: 39% of tumors were found to be aneuploid. Mean proliferation fraction was distinctly higher in euploid tumors (15.6%) than in normal tissue (6.1%). DNA ploidy pattern correlated significantly (p < 0.05) with histological grading. With increasing tumor size the clonal spectrum changed as well: Tetraploid cell lines fell from 40% to 28%. The number of triploid clones rose from 33% to 56%. CONCLUSION: Based on selection of tri- and hypertetraploid carcinomas, a high-risk-group for tumor recurrence can be associated within the predominating T2/3 G2 kidney tumors. The aim is to treat these patients following curative surgery at the stage of probable micro-metastases while keeping risk of overtreatment as low as possible.

Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma.

BACKGROUND: Bispecific antibodies--consisting of a F(ab')-fragment derived from a monoclonal antibody against a tumor epitope as well as of another antibody against a cytotoxic trigger molecule on immune effector cells--can improve the effectiveness of antibody-based tumor therapy. MATERIALS AND METHODS: We used bispecific antibodies with one specifity against the EGF-receptor, which is overexpressed on the majority of renal cell carcinomas, and another specifity against Fc receptors on human leukocytes (Fc gamma RI/CD64; Fc gamma RIII/CD16 and Fc alpha RI/CD89). As source of effector cells, whole blood from patients treated with G-CSF, GM-CSF or IL2/IFN-alpha was used in 51Cr- release assays using various renal cancer cell lines as tumor targets. Further experiments with Percoll-isolated granulocytes or mononuclear cells from the same donors were performed in order to identify the active effector cell populations. RESULTS: Compared with conventional monoclonal EGF-R directed antibodies (murine IgG2a, humanized IgG1), bispecific antibodies induced significantly enhanced cytotoxicity. Highest amounts of tumor cell killing were observed using whole blood from patients treated with G-CSF or GM-CSF in combination with an [Fc alpha RI x EGF-R] bispecific antibody. Under these conditions, granulocytes constituted the most active effector cell population. CONCLUSION: The combination of myeloid growth factors and bispecific antibodies offer a promising new approach for the treatment of advanced renal cell carcinoma.

HLA class II antibodies recruit G-CSF activated neutrophils for treatment of B cell malignancies.

Monoclonal antibodies offer the potential to improve specificity of oncological therapy. However, future success in the clinic depends on enhancing antibody effector functions. Here, we suggest that target antigen selection may influence recruitment of effector cells for antibody therapy, and may improve the outcome of antibody treatment in patients. Comparing a wide range of antibodies to different B cell antigens, we found most were able to mediate antibody dependent cellular cytotoxicity (ADCC) with blood mononuclear cells (MNC). In direct contrast, however, polymorphonuclear granulocytes (PMN) from the same donors showed ADCC only with HLA class II antibodies. Based on this observation, we propose a therapeutic strategy with a combination of HLA class antibodies and G-CSF, the latter being required to increase number and activational state of neutrophils. In particular, we suggest using bispecific antibodies (BsAb) in which one arm binds to HLA class II on tumor cells, and the second to FcgammaRI on activated effector cells. The clinical potential of this approach for the treatment of B cell malignancies looks most attractive.

HLA class II as potential target antigen on malignant B cells for therapy with bispecific antibodies in combination with granulocyte colony-stimulating factor.

We have investigated the capacity of polymorphonuclear phagocytes (PMN) to lyse malignant B-cell lines using antibodies and antibody derivates to a range of different B-cell antigens. PMN were found to mediate lysis of all tested B-cell lines in the presence of HLA class II antibodies L227, L243, F3.3, and CR3/43. Target cell lysis was significantly enhanced when PMN isolated during granulocyte colony-stimulating factor (G-CSF) treatment were compared with PMN from healthy donors. Only G-CSF primed PMN, expressing Fc gamma RI (CD64), lysed B cells in the presence of monoclonal antibody (MoAb) 1D10 or Lym-1 to HLA class II related epitopes. Remarkably, PMN were consistently unable to kill malignant B cells with antibodies to the B-cell related antigens CD19, CD20, CD21, CD37, and CD38. These target antigen restriction was not observed with mononuclear effector cells, which mediated cytotoxicity with antibodies to HLA class II, but also with mouse/human chimeric constructs to CD19, CD37, and CD38. Blocking studies with Fc gamma RI antibodies and reverse antibody-dependent cellular cytotoxicity (ADCC) experiments against Fc gamma R antibody expressing hybridoma targets confirmed the pivotal role of Fc gamma RI in enhanced killing by G-CSF primed neutrophils. Bispecific antibodies (BsAb) with one specificity for Fc gamma RI, and another for a tumor associated antigen, offer an interesting approach to improve effector cell recruitment for immunotherapy. In our studies, very effective lysis was observed with G-CSF primed PMN and an [HLA class II x Fc gamma RI] BsAb. The therapeutic implications of these findings and the possible use of BsAb in combination with G-CSF are discussed.

[Prognostic importance of diagnostic functional and social parameters for occupational rehabilitation of heart patients. Results of studies and practical applications for rehabilitation counseling]. / Prognostische Bedeutung funktions-diagnostischer und sozialer Parameter für die berufliche Wiedereingliederung von Herzkranken. Studienergebnisse und praktische Umsetzung in der Rehabilitationsberatung.

Vocational and social reintegration is one of the main targets of cardiac rehabilitation programs. As prognosis bases on objective pathophysiological data and psychosocial data, those data have to be used in the practice of cardiologists and rehabilitation workers. The relevant diagnostic parameters are demonstrated in this publication.