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Investigating strangeness enhancement with multiplicity in pp collisions using angular correlations
(2024)
A study of strange hadron production associated with hard scattering processes and with the underlying event is conducted to investigate the origin of the enhanced production of strange hadrons in small collision systems characterised by large charged-particle multiplicities. For this purpose, the production of the single-strange meson K0S and the double-strange baryon Ξ± is measured, in each event, in the azimuthal direction of the highest-pT particle (``trigger" particle), related to hard scattering processes, and in the direction transverse to it in azimuth, associated with the underlying event, in pp collisions at s√=5.02 TeV and s√=13 TeV using the ALICE detector at the LHC. The per-trigger yields of K0S and Ξ± are dominated by the transverse-to-leading production (i.e., in the direction transverse to the trigger particle), whose contribution relative to the toward-leading production is observed to increase with the event charged-particle multiplicity. The transverse-to-leading and the toward-leading Ξ±/K0S yield ratios increase with the multiplicity of charged particles, suggesting that strangeness enhancement with multiplicity is associated with both hard scattering processes and the underlying event. The relative production of Ξ± with respect to K0S is higher in transverse-to-leading processes over the whole multiplicity interval covered by the measurement. The K0S and Ξ± per-trigger yields and yield ratios are compared with predictions of three different phenomenological models, namely PYTHIA 8.2 with the Monash tune, PYTHIA 8.2 with ropes and EPOS LHC. The comparison shows that none of them can quantitatively describe either the transverse-to-leading or the toward-leading yields of K0S and Ξ±.
The first measurement of the impact-parameter dependent angular anisotropy in the decay of coherently photoproduced ρ0 mesons is presented. The ρ0 mesons are reconstructed through their decay into a pion pair. The measured anisotropy corresponds to the amplitude of the cos(2ϕ) modulation, where ϕ is the angle between the two vectors formed by the sum and the difference of the transverse momenta of the pions, respectively. The measurement was performed by the ALICE Collaboration at the LHC using data from ultraperipheral Pb−Pb collisions at a center-of-mass energy of sNN−−−√ = 5.02 TeV per nucleon pair. Different impact-parameter regions are selected by classifying the events in nuclear-breakup classes. The amplitude of the cos(2ϕ) modulation is found to increase by about one order of magnitude from large to small impact parameters. Theoretical calculations, which describe the measurement, explain the cos(2ϕ) anisotropy as the result of a quantum interference effect at the femtometer scale that arises from the ambiguity as to which of the nuclei is the source of the photon in the interaction.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
Diese Arbeit benutzt mikrometeorologische, pflanzenökologische und bodenhydrologische Messungen als Mittel zum Prozessverständnis. Der langfristige Flussmessstandort Ankerstation Tharandter Wald (von 120 jährigen Fichten dominiert) zeigt die große Dynamik der Landoberflächen-Atmosphären-Wechselwirkungen wie auch ihre Klimaeffekte auf die Verteilung der turbulenten Wärmeströme, die Kohlenstoffsequestrierung und die Evapotranspiration (ET). Klimawerte, Phänologie und Flüsse unterstützen die Einteilung des Jahres in eine ‚aktive Phase’ (April–September) und eine ‚Ruhephase’ (Oktober– März): Kohlenstoffsequestrierung, zur Verfügung stehende Energie (Strahlungsbilanz) und fühlbarer Wärmestrom sind in der Ruhephase praktisch vernachlässigbar. Nur ET zeigt einen signifikanten Beitrag zur Jahresbilanz (25 % der aktiven Phase) aus der Interzeption (Evaporation von benetzten Nadeln), die vom fühlbaren Wärmestrom aus der Atmosphäre angetrieben wird. Die zwischenjährliche Variation der Flüsse ist im Allgemeinen klein (z. B. 500–650 gC m-2 yr -1) C-Aufnahme), selbst mit dem starken Dürrejahr 2003 (400 gC m-2) oder dem Effekt der Durchforstung 2002. Verglichen mit der Buche erreicht die Fichte – zumindest in der aktiven Periode – ähnliche Werte von ET aber niedrigere bei der C-Aufnahme. Die Kronentraufe beträgt bei der Fichte nur ca. 55 % des Niederschlages, bei der Buche summieren sich ca. 40 % Kronentraufe und knapp 25 % Stammabfluss zu etwa 65 % Bestandesniederschlag. Dieser Unterschied erklärt möglicherweise die im Allgemeinen höhere Bodenfeuchte am Buchenstandort. Als Resultat aus dieser Arbeit werden Modelle mit ausreichender Komplexität empfohlen, welche Bestandesstruktur und Phänophasen berücksichtigen. Das ist eine Voraussetzung für eine bessere Berücksichtigung von Wäldern mit ihren Landoberflächen-
Atmosphären-Wechselwirkungen, z. B. in Klimamodellen.
Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.