DX5+NKT cells display phenotypical and functional differences between spleen and liver as well as NK1.1-Balb/c and NK1.1+ C57Bl/6 mice

These results show that DX5+NKT cells are a heterogeneous population, depending on the dedicated organ and mouse strain, that has diverse functional capacity

Conceptual design of a nonscaling fixed field alternating gradient accelerator for protons and carbon ions for charged particle therapy

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.The conceptual design for a nonscaling fixed field alternating gradient accelerator suitable for charged particle therapy (the use of protons and other light ions to treat some forms of cancer) is described.EPSR

Cytokine Response of Natural Killer Cells to Hepatitis B Virus Infection Depends on Monocyte Co-Stimulation

Hepatitis B virus (HBV) is a major driver of chronic hepatic inflammation, which regularly leads to liver cirrhosis or hepatocellular carcinoma. Immediate innate immune cell response is crucial for the rapid clearance of the infection. Here, natural killer (NK) cells play a pivotal role in direct cytotoxicity and the secretion of antiviral cytokines as well as regulatory function. The aim of this study was to further elucidate NK cell responses triggered by an HBV infection. Therefore, we optimized HBV in vitro models that reliably stimulate NK cells using hepatocyte-like HepG2 cells expressing the Na+-taurocholate co-transporting polypeptide (NTCP) and HepaRG cells. Immune cells were acquired from healthy platelet donors. Initially, HepG2-NTCP cells demonstrated higher viral replication compared to HepaRG cells. Co-cultures with immune cells revealed increased production of interferon-γ and tumor necrosis factor-α by NK cells, which was no longer evident in isolated NK cells. Likewise, the depletion of monocytes and spatial separation from target cells led to the absence of the antiviral cytokine production of NK cells. Eventually, the combined co-culture of isolated NK cells and monocytes led to a sufficient cytokine response of NK cells, which was also apparent when communication between the two immune cell subpopulations was restricted to soluble factors. In summary, our study demonstrates antiviral cytokine production by NK cells in response to HBV+ HepG2-NTCP cells, which is dependent on monocyte bystander activation

Successful auxiliary two-staged partial resection liver transplantation (ASPIRE-LTx) for end-stage liver disease to avoid small-for-size situations

Background Risks for living-liver donors are lower in case of a left liver donation, however, due to lower graft volume, the risk for small-for-size situations in the recipients increases. This study aims to prevent small-for-size situations in recipients using an auxiliary two-staged partial resection liver transplantation (LTX) of living-donated left liver lobes. Case presentation Two patients received a two-stage auxiliary LTX using living-donated left liver lobes after left lateral liver resection. The native extended right liver was removed in a second operation after sufficient hypertrophy of the left liver graft had occurred. Neither donor developed postoperative complications. In both recipients, the graft volume increased by an average of 105% (329 ml to 641 ml), from a graft-to-body-weight ratio of 0.54 to 1.08 within 11 days after LTX, so that the remnant native right liver could be removed. No recipient developed small-for-size syndrome; graft function and overall condition is good in both recipients after a follow-up time of 25 months. Conclusions Auxiliary two-staged partial resection LTX using living-donor left lobes is technically feasible and can prevent small-for-size situation. This new technique can expand the potential living-donor pool and contributes to increase donor safety

The nuclear energy density functional formalism

The present document focuses on the theoretical foundations of the nuclear energy density functional (EDF) method. As such, it does not aim at reviewing the status of the field, at covering all possible ramifications of the approach or at presenting recent achievements and applications. The objective is to provide a modern account of the nuclear EDF formalism that is at variance with traditional presentations that rely, at one point or another, on a {\it Hamiltonian-based} picture. The latter is not general enough to encompass what the nuclear EDF method represents as of today. Specifically, the traditional Hamiltonian-based picture does not allow one to grasp the difficulties associated with the fact that currently available parametrizations of the energy kernel $E[g',g]$ at play in the method do not derive from a genuine Hamilton operator, would the latter be effective. The method is formulated from the outset through the most general multi-reference, i.e. beyond mean-field, implementation such that the single-reference, i.e. "mean-field", derives as a particular case. As such, a key point of the presentation provided here is to demonstrate that the multi-reference EDF method can indeed be formulated in a {\it mathematically} meaningful fashion even if $E[g',g]$ does {\it not} derive from a genuine Hamilton operator. In particular, the restoration of symmetries can be entirely formulated without making {\it any} reference to a projected state, i.e. within a genuine EDF framework. However, and as is illustrated in the present document, a mathematically meaningful formulation does not guarantee that the formalism is sound from a {\it physical} standpoint. The price at which the latter can be enforced as well in the future is eventually alluded to.Comment: 64 pages, 8 figures, submitted to Euroschool Lecture Notes in Physics Vol.IV, Christoph Scheidenberger and Marek Pfutzner editor

Search for the electric dipole excitations to the 3s1/2⊗[21+⊗31−]3s_{1/2} \otimes [2^{+}_{1} \otimes 3^{-}_{1}] multiplet in 117^{117}Sn

The odd-mass $^{117}$Sn nucleus was investigated in nuclear resonance fluorescence experiments up to an endpoint energy of the incident photon spectrum of 4.1 MeV at the bremsstrahlung facility of the Stuttgart University. More than 50 mainly hitherto unknown levels were found. From the measurement of the scattering cross sections model independent absolute electric dipole excitation strengths were extracted. The measured angular distributions suggested the spins of 11 excited levels. Quasi-particle phonon model calculations including a complete configuration space were performed for the first time for a heavy odd-mass spherical nucleus. These calculations give a clear insight in the fragmentation and distribution of the $E1$, $M1$, and $E2$ excitation strength in the low energy region. It is proven that the $1^{-}$ component of the two-phonon $[2^{+}_{1} \otimes 3^{-}_{1}]$ quintuplet built on top of the $1/2^{+}$ ground state is strongly fragmented. The theoretical calculations are consistent with the experimental data.Comment: 10 pages, 5 figure

ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) does not affect proliferation, apoptosis, or angiogenesis as compared to standard liver resection for colorectal liver metastases

Background: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a novel two-stage strategy to induce rapid hypertrophy of the future liver remnant (FLR) when patients are in danger of postoperative liver failure due to insufficient FLR. However, the effects of ALPPS on colorectal liver metastases (CRLM) are not clear so far. The aim of our study was to determine whether ALPPS induces proliferation, apoptosis, or vascularization compared to standard (one-stage) liver resection. Methods: Six patients who underwent ALPPS were matched with 12 patients undergoing standard liver resection regarding characteristics of the metastases (size, number), time of appearance (syn-/metachronous), preoperative chemotherapy, primary tumor (localization, TNM stage, grading), and patient variables (gender, age). The largest resected metastasis was used for the analyses. Tissue was stained for tumor cell proliferation (Ki67), apoptosis (TUNEL, caspase-3), vascularization (CD31), and pericytes (alpha SMA). Results: Vascularization (CD31; p = 0.149), proliferation (Mib-1; p = 0.244), and aSMA expression (p = 0.205) did not significantly differ between the two groups, although a trend towards less proliferation and aSMA expression was observed in patients undergoing ALPPS. Concerning apoptosis, caspase-3 staining showed significantly fewer apoptotic cells upon ALPPS (p < 0.0001), but this was not confirmed by TUNEL staining (p = 0.7344). Conclusions: ALPPS does not induce proliferation, apoptosis, or vascularization of CRLM when compared to standard liver resection

HCC recurrence in HCV‐infected patients after liver transplantation: SiLVER Study reveals benefits of sirolimus in combination with CNIs – a post‐hoc analysis

Factors affecting outcomes in liver transplant (LTx) recipients with hepatocellular carcinoma (HCC) and hepatitis C viral (HCV) infection include the choice of immunosuppression. Here, we analyzed the HCV+ subgroup of patients from the randomized controlled, international SiLVER Study. We performed a post hoc analysis of 166 HCV+ SiLVER Study patients regarding HCC outcome after LTx. Control patients (group A: n = 88) received mTOR inhibitor (mTORi)-free, calcineurin inhibitor (CNI)-based versus sirolimus-based immunosuppression (group B: n = 78). We found no significant difference regarding HCV-RNA titers between group A and B. Since no effect in group B could be due to variable sirolimus dosing, we split group B into patients receiving sirolimus-based immunosuppression + CNIs for >50% (B1; n = 44) or <50% (B2; n = 34) of the time. While there remained no difference in HCV-RNA titer between groups, HCC recurrence-free survival in group B1 (81.8%) was markedly better versus both group A (62.7%; P = 0.0136) and group B2 (64.7%; P = 0.0326); Interestingly, further subgroup analysis revealed an increase (P = 0.0012) in liver enzyme values in group B2. Taken together, in HCV-infected patients with HCC and LTx, mTORi immunosuppression + CNIs yields excellent outcomes. Unexpectedly, higher levels of liver inflammation and poorer outcomes occur with mTORi monotherapy in the HCV+ subgroup

Cancer-associated cells release citrate to support tumour metastatic progression

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter’s major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression

Good outcomes after repeated pediatric liver retransplantations: A justified procedure even in times of organ shortage

Background Pediatric liver transplantations generally represent advanced surgery for selected patients. In case of acute or chronic graft failure, biliary or vessel complications, a retransplantation (reLT) can be necessary. In these situations massive adhesions, critical patient condition or lack of good vessels for anastomosis often are problematic. Methods Between 2008 and 2021, 208 pediatric patients received a liver transplantation at our center. Retrospectively, all cases with at least one retransplantation were identified and stored in a database. Indication, intra- and postoperative course and overall survival (OS) were analyzed. Results Altogether 31 patients (14.9%) received a reLT. In 22 cases only one reLT was done, 8 patients received 2 reLTs and 1 patient needed a fourth graft. Median age for primary transplantation, first, second and third reLT was 14 (range: 1–192 months), 60.5 (range: 1–215 months), 58.5 (range: 14–131 months) and 67 months, respectively. Although biliary atresia (42%) and acute liver failure (23%) represented the main indications for the primary liver transplantation, acute and chronic graft failure (1st reLT: 36%, 2nd reLT: 38%), hepatic artery thrombosis (1st reLT: 29%, 2nd reLT: 25%, 3rd reLT: 100%) and biliary complications (1st reLT: 26%, 2nd reLT: 37%) were the most frequent indications for reLT. OS was 81.8% for patients with 1 reLT, 87.5% with 2 reLTs and 100% with 3 reLTs. Conclusion Pediatric liver retransplantation is possible with a good outcome even after multiple retransplantations in specialized centers. Nevertheless, careful patient and graft selection, as well as good preoperative conditioning, are essential