[Retracted] Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti­apoptotic proteins.

Following the publication of the above article and a corrigendum that was published in October 2023 to address the issue of misplaced control ß­actin western blots comparing between Figs. 3 and 4A (doi: 10.3892/or.2023.8646), an attentive reader drew to the authors' attention that the first author had apparently made additional unreported corrections to the revised version of Fig. 4 presented in the corrigendum. Although these image discrepancies did not alter the study's primary conclusions, they were such that they did cast doubt on the data's integrity. Consequently, the authors have decided to retract the paper and the Editor of Oncology Reports has agreed to the authors' request. The authors deeply regret any confusion or inconvenience this retraction may cause, and offer their sincere apologies to the Editor of Oncology Reports and the readership. [Oncology Reports 37: 3660­3666, 2017; DOI: 10.3892/or.2017.5622].

[Corrigendum] Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti­apoptotic proteins.

Following the publication of this article, an interested reader drew to the authors' attention that, in Figs. 3 and 4A on p. 3664, the respective ß­actin controls for the cell lines TFK­1 and HuCCT­1 appeared to have mixed up, comparing the western blots between the two figures. After re­examining their data, the authors have realized that the control blots in Fig. 4A were inadvertently presented the wrong way around. The corrected version of Fig. 4, showing the correctly presented western blotting data in Fig. 4A, is shown on the next page. Note that this error did not grossly affect the results or the conclusions reported in this paper. The authors sincerely apologize for the error that was introduced during the preparation of this figure, and thank the Editor of Oncology Reports for allowing them the opportunity to publish a corrigendum. Furthermore, they regret any inconvenience caused to the readership. [Oncology Reports 37: 3660­3666, 2017; DOI: 10.3892/or.2017.5622].

Improving adherence to immunosuppression after liver or kidney transplantation in individuals with impairments in personality functioning - A randomized controlled single center feasibility study.

Introduction: Although adherence to immunosuppressive medication is the key factor for long-term graft survival today, 20-70% of transplant recipients are non-adherent to their immunosuppressive medication. Objective: A prospective, randomized, controlled single-center feasibility study was designed to evaluate the impact of a step guided multicomponent interprofessional intervention program for patients after kidney or liver transplantation on adherence to their immunosuppressive medication in daily clinical practice. Materials and methods: The intervention consisted of group therapy and daily training as well as individual sessions in a step guided approach. The primary endpoint of the study was adherence to immunosuppression as assessed with the "Basel Assessment of Adherence to Immunosuppressive Medications Scale" (BAASIS). The coefficient of variation (CV%) of Tacrolimus (TAC) through levels and the level of personality functioning was a secondary endpoint. We conducted six monthly follow-up visits. Results: Forty-one age- and sex-matched patients [19 females, 58.5 (SD = 10.56) years old, 22 kidney- and 19 liver transplantation] were randomized to the intervention- (N = 21) or control-group (N = 20). No differences between intervention- and control groups were found in the primary endpoint adherence and CV% of TAC. However, in further exploratory analyses, we observed that individuals with higher impairments in personality functioning showed higher CV% of TAC in the controls. The intervention might compensate personality-related susceptibility to poor adherence as evident in CV% of TAC. Discussion: The results of the feasibility study showed that this intervention program was highly accepted in the clinical setting. The Intervention group could compensate higher CV% of TAC after liver or kidney transplantation in individuals with lower levels of personality functioning and non-adherence. Clinical trial registration: ClinicalTrials.gov, identifier NCT04207125.

Probiotic Supplementation Attenuates Chemotherapy-Induced Intestinal Mucositis in an Experimental Colorectal Cancer Liver Metastasis Rat Model.

The use of chemotherapeutic agents is of paramount importance when treating colorectal cancer (CRC). Unfortunately, one of the most frequent chemotherapy (CTx) side effects is intestinal mucositis (IM), which may present with several clinical symptoms such as nausea, bloating, vomiting, pain, and diarrhea and even can result in life-threatening complications. There is a focused scientific effort towards developing new therapies to prevent and treat IM. The aim of this study was to assess the outcomes of probiotic supplementation on CTx-induced IM in a CRC liver metastasis rat model. Six-week-old male Wistar rats received either a multispecies probiotic or placebo mixture. On the 28th experiment day, rats received FOLFOX CTx, and afterwards, the severity of diarrhea was evaluated twice daily. Stool samples were collected for further microbiome analysis. Additionally, immunohistochemical stainings of ileum and colon samples with were performed with MPO, Ki67, and Caspase-3 antibodies. Probiotic supplementation alleviates the severity and length of CTx-induced diarrhea. Additionally, probiotics significantly reduced FOLFOX-induced weight and blood albumin loss. Furthermore, probiotic supplementation mitigated CTx-induced histological changes in the gut and promoted intestinal cell regeneration. This study shows that multispecies probiotic supplementation attenuates FOLFOX-induced IM symptoms by inhibiting apoptosis and promoting intestinal cell proliferation.

Combined Femtosecond Laser Glass Microprocessing for Liver-on-Chip Device Fabrication.

Nowadays, lab-on-chip (LOC) devices are attracting more and more attention since they show vast prospects for various biomedical applications. Usually, an LOC is a small device that serves a single laboratory function. LOCs show massive potential for organ-on-chip (OOC) device manufacturing since they could allow for research on the avoidance of various diseases or the avoidance of drug testing on animals or humans. However, this technology is still under development. The dominant technique for the fabrication of such devices is molding, which is very attractive and efficient for mass production, but has many drawbacks for prototyping. This article suggests a femtosecond laser microprocessing technique for the prototyping of an OOC-type device-a liver-on-chip. We demonstrate the production of liver-on-chip devices out of glass by using femtosecond laser-based selective laser etching (SLE) and laser welding techniques. The fabricated device was tested with HepG2(GS) liver cancer cells. During the test, HepG2(GS) cells proliferated in the chip, thus showing the potential of the suggested technique for further OOC development.

Non-colorectal liver metastases: A review of interventional and surgical treatment modalities.

Liver metastases (LM) occur in up to 90% either simultaneously with the diagnosis of the primary tumor or at a later time-point. While resection of colorectal LM and resection or transplantation of neuroendocrine LM is part of a standard therapy with a 5-year patient survival of up to 80%, resection of non-colorectal and non-neuroendocrine LM is still discussed controversially. The reason for it is the significantly lower survival benefit of all different tumor entities depending on the biological aggressiveness of the tumor. Randomized controlled trials are lacking. However, reviews of case series with ≥100 liver resections are available. They show a 5-year patient survival of up to 42% compared to only <5% in patients without treatment. Risk factors for poor survival include the type of primary tumor, a short interval between resection of the primary tumor and liver resection, extrahepatic manifestation of the tumor, number and size of the LM, and extent of liver resection. Overall, it has recently been shown that a good patient selection, the technical advances in surgical therapy and the use of a risk score to predict the prognosis lead to a significantly better outcome so that it is no longer justified not to offer liver resection to patients with non-colorectal, non- endocrine LM. Since modern therapy of LM is multimodal, the optimal therapeutic approach is decided individually by a multidisciplinary team consisting of visceral surgeons, oncologists, interventional radiologists and radiologists as part of a tumor board.

Experimental Static Cold Storage of the Rat Uterus: Protective Effects of Relaxin- or Erythropoietin-Supplemented HTK-N Solutions.

Uterus transplantation (UTx) is the only treatment method for women with absolute uterine infertility. Currently, the number of grafts retrieved from deceased donors is increasing; hence, prolonged cold ischemia time is inevitable. Thus, this study was designed to assess the effect of the novel relaxin (RLN)- or erythropoietin (EPO)-supplemented Custodiol-N (HTK-N) solutions in an experimental uterus static cold storage (SCS) model. A total of 15 Sprague Dawley rats were used. Uterus horns were randomly assigned into three groups (n = 10/group). SCS was performed by keeping samples at 4 °C in HTK-N solution without or with different additives: 10 IU/mL EPO or 20 nM RLN. Tissue samples were taken after 8 and 24 h of preservation. Uterine tissue histology, and biochemical and immunohistochemical markers were analyzed. No significant differences in SCS-induced tissue damage were observed between groups after 8 h of preservation. Uterine tissue histology, MDA, SOD levels and the TUNEL-positive cell number showed severe damage in HTK-N without additives after 24 h of preservation. This damage was significantly attenuated by adding RLN to the preservation solution. EPO showed no favorable effect. Our study shows that RLN as an additive to an HTK-N solution can serve as an effective uterine tissue preservative in the uterus SCS setting.

The impact of COVID-19 on liver transplantation programs in Austria.

BACKGROUND: Coronavirus disease of 2019 (COVID-19) has affected liver disease management. The impact of the COVID-19 pandemic on the Austrian orthotopic liver transplantation (OLT) programs, however, has not been systematically investigated. METHODS: All patients listed for OLT in Austria during 2020-2021 were studied. Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing, vaccinations, infections, mortality and the overall number of OLTs (vs. pre-COVID-19: 2015-2019) were analyzed. RESULTS: Overall, 490 patients (median age: 58.0 years, 70.4% men, hepatocellular carcinoma: 27.3%) were listed for OLT in Austria in 2020-2021. Alcohol-related cirrhosis (35.3%), cholestatic (16.7%) and viral liver disease (13.9%) were the main etiologies. Of the patients 61.2% underwent OLT and 8.8% died while on the waiting list. The number of OLTs performed during COVID-19 (2020: n = 150; 2021: n = 150) remained unchanged compared to pre-COVID-19 (median: n = 152). Among waiting list patients, 7.7% (n = 31/401) were diagnosed with COVID-19 and 7 (22.6%) of these patients died. By the end of 2021, 45.1% (n = 176/390; 82.8% mRNA vaccinations) and 28.8% (105/365) of patients received 2 and 3 SARS-CoV­2 vaccinations, respectively. After two SARS-CoV­2 vaccinations, antibodies more often remained undetectable in patients vaccinated post-OLT (25.6% vs. 6.5% in patients vaccinated pre-OLT; p = 0.034). Patients with three vaccinations after OLT had lower antibody titers than patients vaccinated pre-OLT (post-OLT: 513.5, IQR 44.4-2500.0 vs. pre-OLT: 2500.0, IQR 1462.0-2500.0 BAU/mL; p = 0.020). CONCLUSION: The number of OLTs in Austria remained unchanged during COVID-19. SARS-CoV­2 infections were rare but associated with high mortality in patients on the Austrian OLT waiting lists. SARS-CoV­2 vaccination rates at the end of 2021 were suboptimal, while serological response was better in patients vaccinated pre-OLT vs. post-OLT.

[Update: Immunosuppression in organ transplantation]. / Update: Immunsuppression bei Organtransplantationen.

Immunosuppression is an essential prerequisite for successful transplantation. In order to reduce the sometimes-considerable side effects, combination therapies with different agents are used. This article aims to provide an up-to-date overview of immunosuppression after liver and kidney transplantation.

Sulforaphane has an additive anticancer effect to FOLFOX in highly metastatic human colon carcinoma cells.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Patients with CRC may need chemotherapy (CTx) in a neoadjuvant, adjuvant or palliative setting through the course of the disease. Unfortunately, its effect is limited by chemoresistance and chemotoxicity. Novel more effective and non­toxic CTx regimens are needed to further improve CRC treatment outcomes. Thus, the present study was designed to test the hypothesis that non­toxic sulforaphane (SF) is effective against CRC and has additive effects in combination with conventional 5­fluorouracil, oxaliplatin and folinic acid (FOLFOX) CTx in vitro. Highly metastatic human colon cancer cells, CX­1, and fibroblasts were treated with FOLFOX ± SF. Cell viability was assessed using an MTT assay. The level of apoptosis and the expression of apoptotic proteins were measured by TUNEL assay and quantitative PCR analysis. Aldehyde dehydrogenase isoform 1 (ALDH1) and multidrug resistance protein 2 (MRP2) levels were evaluated. The ability of cells to form spheroids was measured in three­dimensional cell culture. SF alone and in combination with FOLFOX effectively decreased the viability of the CX­1 cells, promoted apoptosis within the CX­1 cells, prevented cellular spheroid formation and decreased ALDH1 activity. However, SF promoted MRP2 expression and protein levels. In conclusion, SF together with conventional FOLFOX has additive anticancer effects against highly metastatic human CRC in vitro.

Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis.

Background: Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). Methods: The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. Results: The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34-0.76; p = 0.001; I 2 = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17-0.67; p = 0.002; I 2 = 0%) compared to SCS. Conclusion: Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.

Probiotic Supplementation Suppresses Tumor Growth in an Experimental Colorectal Cancer Liver Metastasis Model.

Colorectal cancer (CRC) ranks third in incidence and second in mortality of all cancers worldwide. At the time of primary diagnosis, around 20% of patients already have metastatic CRC and only around 20% are candidates for radical resection. Thus, most of the patients have to undergo chemotherapy (CTx). Due to chemoresistance and side effects, novel treatment additives are crucial for controlling the disease and prolonging patient survival. The aim of this study was to evaluate probiotic supplementation and its antitumorigenic effects in an experimental CRC liver metastasis model. Six-week-old male Wistar rats received either a multispecies probiotic (1.2 × 109 CFU/daily) or placebo mixture. On day 14 of the experiment, rat CRC cells (CC531) were implanted under the liver capsule later treated by FOLFOX CTx. Change in tumor volume was measured by performing micro computed tomography (micro-CT) scanning on experimental days 28 and 34. Additionally, immunohistochemical staining with anti-MPO, anti-Ki67, and anti-CD31 were performed. Tumor apoptosis was evaluated using TUNEL staining. Micro-CT image analysis indicates that probiotic supplementation significantly inhibits tumor growth. No synergistic effects between probiotic supplementation and FOLFOX CTx was observed. Reduced tumor volume was achieved by inhibiting angiogenesis, as tumor microvascular density was significantly lower in rats receiving probiotic supplementation. This study shows that a multispecies probiotic mixture significantly reduces angiogenesis and inhibits CRC liver metastasis growth in an experimental rat model.

Relaxin and Erythropoietin Significantly Reduce Uterine Tissue Damage during Experimental Ischemia-Reperfusion Injury.

Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia-reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 µg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI.

Necroptosis in Solid Organ Transplantation: A Literature Overview.

Ischemia-reperfusion injury (IRI) is encountered in various stages during solid organ transplantation (SOT). IRI is known to be a multifactorial inflammatory condition involving hypoxia, metabolic stress, leukocyte extravasation, cellular death (including apoptosis, necrosis and necroptosis) and an activation of immune response. Although the cycle of sterile inflammation during IRI is consistent among different organs, the underlying mechanisms are poorly understood. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be crucial in the implementation of necroptosis. Moreover, apart from "silent" apoptotic death, necrosis also causes sterile inflammation-necroinflammation, which is triggered by various damage-associated molecular patterns (DAMPs). Those DAMPs activate the innate immune system, causing local and systemic inflammatory responses, which can result in graft failure. In this overview we summarize knowledge on mechanisms of sterile inflammation processes during SOT with special focus on necroptosis and IRI and discuss protective strategies.

B Cell Composition Is Altered After Kidney Transplantation and Transitional B Cells Correlate With SARS-CoV-2 Vaccination Response.

BACKGROUND: The COVID-19 pandemic has major implications on kidney transplant recipients (KTRs) since they show increased mortality due to impaired immune responses to SARS-CoV-2 infection and a reduced efficacy of SARS-CoV-2 vaccination. Surprisingly, dialysis patients have shown superior seroconversion rates after vaccination compared to KTRs. Therefore, we investigated peripheral blood B cell (BC) composition before and after kidney transplantation (KT) and aimed to screen the BC compartment to explain impaired antibody generation. METHODS: A total of 105 patients were recruited, and multicolor flow cytometric phenotyping of peripheral venous blood BC subpopulations was performed before and 1 year after KT. Complete follow-up was available for 71 individuals. Anti-SARS-CoV-2 antibodies were collected retrospectively and were available for 40 subjects, who had received two doses of an mRNA-based vaccine (BNT162b2 or mRNA-1273). RESULTS: Overall, relative BC frequencies within lymphocytes decreased, and their absolute counts trended in the same direction 1 year after KT as compared to CKD G5 patients. Frequencies and absolute numbers of naïve BCs remained stable. Frequencies of double negative BCs, a heterogeneous subpopulation of antigen experienced BCs lacking CD27 expression, were increased after KT, yet their absolute counts were similar at both time points. Transitional BCs (TrBCs) and plasmablasts were significantly reduced after KT in absolute and relative terms. Memory BCs were affected differently since class-switched and IgM-only subsets decreased after KT, but unswitched and IgD-only memory BCs remained unchanged. CD86+ and CD5+ expression on BCs was downregulated after KT. Correlational analysis revealed that TrBCs were the only subset to correlate with titer levels after SARS-CoV-2 vaccination. Responders showed higher TrBCs, both absolute and relative, than non-responders. CONCLUSION: Together, after 1 year, KTRs showed persistent and profound compositional changes within the BC compartment. Low TrBCs, 1 year after KT, may account for the low serological response to SARS-CoV-2 vaccination in KTRs compared to dialysis patients. Our findings need confirmation in further studies as they may guide vaccination strategies.

Platelet to Lymphocyte Ratio Correlates With Carcinoma Progression in Pancreatic Intra Epithelial Neoplasia.

BACKGROUND/AIM: Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion to pancreatic adenocarcinoma (PDAC). Yet no criteria to quantify patients at risk for progression to PDAC with PanIN exist. Platelet to lymphocyte ratio is an inflammatory marker that has been associated with overall survival in patients with invasive malignancies including pancreatic cancer. Preoperative sarcopenia has been linked to more aggressive diseases in pancreatic neoplasms. We aimed to assess a relation between PLR and sarcopenia as predictors for tumor progression in patients undergoing pancreatic resection for IPMN. PATIENTS AND METHODS: We retrospectively reviewed 102 patients (46 females, 56 males) who underwent pancreatic resection for PanIn. PLR was calculated and quantified using a cutoff of 110, sarcopenia was quantified using the skeletal muscle index (SMI) on preoperative abdominal imaging. Both were co-evaluated with additional demographic, clinical, pathological, and imaging data for possible correlation with PanIN associated PDAC. RESULTS: PLR was significantly elevated in patients with PanIN - associated PDAC (p=0.006). In the multivariate analysis, invasive carcinomas were significantly more prevalent in patients with PLR above 110 (OR=4.06, 95%CI=3.91-4.12, p=0.04). Patients with elevated PLR had a two-times higher risk to die in the postoperative period (HR=2.26, 95%CI=1.04-2.21, p=0.001). Patients with elevated PLR, preoperative jaundice and sarcopenia were the most likely to have PanIN-associated PDAC (OR=3.48, 95%CI=2.98-8.41, p=0.02). CONCLUSION: PLR is an independent predictive marker for the presence of PanIN associated invasive carcinoma.