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Background: Hepatosteatosis is the earliest stage in the pathogenesis of nonalcoholic fatty (NAFLD) and alcoholic liver disease (ALD). As NAFLD is affecting 10-24% of the general population and approximately 70% of obese patients, it carries a large economic burden and is becoming a major reason for liver transplantation worldwide. ALD is a major cause of morbidity and mortality causing 50% of liver cirrhosis and 10% of liver cancer related death. Increasing evidence has accumulated that gut-derived factors play a crucial role in the development and progression of chronic liver diseases., Methods: A selective literature search was conducted in Medline and PubMed, using the terms "nonalcoholic fatty liver disease," "alcoholic liver disease," "lipopolysaccharide," "gut barrier," and "microbiome.", Results: Gut dysbiosis and gut barrier dysfunction both contribute to chronic liver disease by abnormal regulation of the gut-liver axis. Thereby, gut-derived lipopolysaccharides (LPS) are a key factor in inducing the inflammatory response of liver tissue. The review further underlines that endotoxemia is observed in both NAFLD and ALD patients. LPS plays an important role in conducting liver damage through the LPS-TLR4 signaling pathway. Treatments targeting the gut microbiome and the gut barrier such as fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, and intestinal alkaline phosphatase (IAP) represent potential treatment modalities for NAFLD and ALD., Conclusions: The gut-liver axis plays an important role in the development of liver disease. Treatments targeting the gut microbiome and the gut barrier have shown beneficial effects in attenuating liver inflammation and need to be further investigated., (© 2021. The Author(s).)

Background: Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. However, technical aspects of OLT are still subject of ongoing debate and are widely based on personal experience and local institutional protocols., Methods: An international online survey was sent out to all liver transplant centers (n = 52) within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplant Society networks. The survey sought information on center-specific OLT caseload, vascular and biliary reconstruction, graft reperfusion, intraoperative control of hemodynamics, and drain policies., Results: Forty-two centers gave a valid response (81%). Out of these, 50% reported piggy-back and 40.5% total caval replacement as their standard technique. While 48% of all centers generally do not apply veno-venous bypass (vvBP) or temporary portocaval shunt (PCS) during OLT, vvBP/PCS are routinely used in six centers (14%). Portal vein first reperfusion is used in 64%, followed by simultaneous (17%), and retrograde reperfusion (12%). End-to-end duct-to-duct anastomosis without biliary drain (67%) is the most frequently performed method of biliary reconstruction. No significant associations were found between the center caseload and the surgical approach used. The predominant part of the centers (88%) stated that techniques of OLT are not evidence-based and 98% would participate in multicenter clinical trials on these topics., Conclusion: Technical aspects of OLT vary widely among European centers. The extent to which center-specific variation of techniques affect transplant outcomes in Europe should be elucidated further in prospective multicenter trials.

The continuing controversy about surgery for non-colorectal non-neuroendocrine liver metastases (NCRNNE) necessitates identifying risk factors of worsened outcomes to improve patient selection and survival. Prospectively collected data of 167 patients undergoing hepatectomy for NCRNNE were analyzed, and a comparison to a matched population of colorectal liver metastases (CLM) was performed. Overall survival (OS) (35 vs. 54 months; P = 0.008) and recurrence-free survival (RFS) (15 vs. 29 months; P = 0.004) of NCRNNE patients were significantly shorter compared to those with CLM. The best survival was found in the genitourinary (GU; OS, 45 months; RFS, 21 months) NCRNNE subgroup, whereas survival for gastrointestinal (GI) metastases was low (OS, 8 months; RFS, 7 months). Patients with renal cell carcinoma (RCC) showed excellent outcomes when compared to CLM (OS, 50 vs. 51 months; P = 0.901). Extrahepatic disease (EHD) was identified as independent prognostic factor for reducing both RFS (P = 0.040) and OS (P = 0.046). The number of liver lesions (P = 0.024), residual tumor (P = 0.025), and major complications (P = 0.048) independently diminished OS. The degree of survival advantage by surgery is determined by the primary tumor site, EHD, the number of metastases, and residual tumor. Thus-even more than in CLM-these oncological selection criteria must prevail. GU metastases, especially RCC, represent a favorable subgroup.

Background: Extended liver resections in patients with hepatocellular carcinoma (HCC) are problematic due to hepatitis, fibrosis, and cirrhosis. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been promoted as a novel method to induce hypertrophy for patients with extensive colorectal liver metastases, but outcomes in HCC have not been well investigated., Methods: All patients registered in the international ALPPS Registry ( www.alpps.org ) from 2010 to 2015 were studied. Hypertrophy of the future liver remnant, perioperative morbidity and mortality, age, overall survival, and other parameters were compared between patients with HCC and patients with colorectal liver metastases (CRLM)., Results: The study compared 35 patients with HCC and 225 patients with CRLM. The majority of patients undergoing ALPPS for HCC fall into the intermediate-stage category of the Barcelona clinic algorithm. In this study, hypertrophy was rapid and extensive for the HCC patients, albeit lower than for the CRLM patients (47 vs. 76 %; p < 0.002). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality for ALPPS used to treat HCC was almost fivefold higher than for CRLM (31 vs. 7 %; p < 0.001). Multivariate analysis showed that patients older than 61 years had a significantly reduced overall survival (p < 0.004)., Conclusion: The ALPPS approach induces a considerable hypertrophic response in HCC patients and allows resection of intermediate-stage HCC, albeit at the cost of a 31 % perioperative mortality rate. The use of ALPPS for HCC remains prohibitive for most patients and should be performed only for a highly selected patient population younger than 60 years with low-grade fibrosis.

The purpose of the current study is to explore listeners' perception of accented speech in terms of confidence and intelligence. To this end, three groups of listeners were asked to rate speakers of English with various accent strengths based on a 9-point scale in terms of accent magnitude, confidence and intelligence. Results show that the two Jordanian listener groups, unlike the English listeners, reacted similarly toward Jordanian-accented speakers of English. Overall, the three groups tended to link accentedness with perceptions of confidence and intelligence. The findings of this study have significant implications for advocating a tolerant attitude toward speakers of English as a foreign language in the fields of education, employment opportunities, and social justice. It is suggested that stereotyping speakers as inferior in terms of qualities such as confidence and intelligence reflects established listener's bias rather than lack of speaker's intelligibility., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This paper examines the understudied phenomenon of consonant gemination in the pronunciation of English among Levantine Arabic learners of English (LA learners). The very few studies that touched on gemination among LA learners attributed gemination to spelling in the target language (English). This study challenges this analysis and demonstrates that gemination is primarily a phonological phenomenon that is triggered by first language under-represented structural rules as well as Universal Grammar (UG) markedness principles. Data were elicited through semi-structured interviews with three groups of LA learners. Contrary to previous studies (on other phonological aspects), which argue that interference errors decrease over time, findings show that gemination is attested across all groups of LA learners and persists even among advanced learners. Results show that interface phenomena involving more than one phonological level pose a great challenge to second language learners., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tumor angiogenesis is a process that requires migration, proliferation, and differentiation of endothelial cells. We hypothesized that decrease in pancreatic tumor growth due to inhibition of Src activity is associated with the inability of Src kinase to trigger a network of such signaling processes, which finally leads to endothelial cell death and angiogenesis-restricted tumor dormancy. The therapeutic efficacy of Src kinase inhibitor AZM475271 was tested in nude mice orthotopically xenografted with L3.6pl pancreatic carcinoma cells. No liver metastases and peritoneal carcinosis were detected and a significant effect on the average pancreatic tumor burden was observed following treatment with AZM475271, which in turn correlated with a decrease in cell proliferation and an increase in apoptotic endothelial cells. AZM475271 was shown to significantly inhibit migration of human umbilical vein endothelial cells in an in vitro Boyden Chamber cell migration assay. In a rat aortic ring assay we could demonstrate as well inhibition of endothelial cell migration and sprouting following therapy with Src kinase inhibitor at similar doses. The most conclusive anti-angiogenic activity of AZM475271 was demonstrated in vivo (mouse corneal micropocket assay) by showing a marked inhibition of basic fibroblast growth factor-induced neovascularization in response to systemic administration of AZM475271. Furthermore, we could show reduced proliferation of HUVECs determined with the TACS MTT Cell Viability Assay Kit. The blockade of Src kinase significantly reduced the level of VEGF in L3.6pl medium, the effect which was found also in the cell culture supernate from HUVECs. Inhibition of Src kinase by AZM475271 also showed prevention of survival signaling from VEGF and EGF receptors. Treatment with AZM475271 resulted in VEGF - dependent inhibition of tyrosine phosphorylation of FAK. HUVECs were also examined using propidium iodide staining for cell cycle analysis by FACS. Inhibition of Src kinase promoted HUVEC apoptosis in a dose-dependent manner. Taken together, our results suggest that the Src kinase inhibitor AZM475271, in addition to its effects on tumor cells, suppresses tumor growth and metastasis in vitro and in vivo potentially also by anti-angiogenic mechanisms.

Malignant tumors represent a serious problem in transplantation medicine. Tumors passed on by the donor or present in the recipient's history may reappear after transplantation with its need for immunosuppression. On the other hand, in patients with hepatocellular carcinoma (HCC), transplantation is the sole curative therapeutic option. Chronic immunosuppression promotes not only a tendency for the disease to recur, but also the development of various solid and hematological malignancies, and thus makes rigorous prophylactic measures a must. The use of new immunosuppressants (mTOR inhibitors) might, in future, be useful in helping resolve the problem of malignant diseases in organ transplantation.

Lysophosphatidic acid (LPA) is a simple lipid which is endogenously synthesized from lysophosphatidylcholine (LPC) by autotaxin (ATX). LPA mediates a variety of cellular responses through the binding of G protein-coupled LPA receptors (LPA 1 to LPA 6 ). It is considered that LPA receptor-mediated signaling plays an important role in the pathogenesis of human malignancy. Genetic alterations and epigenetic changes of LPA receptors have been detected in some cancer cells as well as LPA per se. Moreover, LPA receptors contribute to the promotion of tumor progression, including cell proliferation, invasion, metastasis, tumorigenicity, and angiogenesis. In recent studies, the activation of LPA receptor-mediated signaling regulates chemoresistance and radiosensitivity in cancer cells. This review provides an updated overview on the roles of LPA receptor-mediated signaling in the regulation of cancer cell functions and its potential utility as a molecular target for novel therapies in clinical cancer approaches., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In our study, we examined the efficacy of mTOR (mammalian target of rapamycin) inhibitors, specifically rapamycin (Rap), compared to calcineurin inhibitors (CNIs) in kidney transplantation. By conducting a comprehensive search across reputable databases (EMBASE, Scopus, PubMed, Cochrane, and Crossref), we gathered data for a six-month post-transplantation period. Our analysis revealed that mTOR inhibitor administration resulted in improved glomerular filtration rate (GFR) and serum creatinine levels. However, it is important to note that the mTOR inhibitor group had a higher incidence of acute rejection after biopsy. Through molecular modeling, we observed that Rap exhibited a superior binding affinity for mTOR compared to CNIs' binding to calcineurin, probably contributing to the transplant rejection. Our meta-analysis supports the cautious use of an optimal mTOR inhibitor in conjunction with careful consideration of clinical features when minimizing CNIs early in the transplantation process. This is because mTOR inhibitors have complementary mechanisms of action, a low nephrotoxicity profile, and favorable outcomes in serum creatinine and GFR, which contribute to improved transplant survival., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Despite significant efforts to control cancer progression and to improve oncology treatment outcomes, recurrence and tumor resistance are frequently observed in cancer patients. These problems are partly related to the presence of cancer stem cells (CSCs). Photodynamic therapy (PDT) has been developed as a therapeutic approach for solid tumors; however, it remains unclear how this therapy can affect CSCs. In this review, we focus on the effects of PDT on CSCs and the possible changes in the CSC population after PDT exposure. Tumor response to PDT varies according to the photosensitizer and light parameters employed, but most studies have reported the successful elimination of CSCs after PDT. However, some studies have reported that CSCs were more resistant to PDT than non-CSCs due to the increased efflux of photosensitizer molecules and the action of autophagy. Additionally, using different PDT approaches to target the CSCs resulted in increased sensitivity, reduction of sphere formation, invasiveness, stem cell phenotype, and improved response to chemotherapy. Lastly, although mainly limited to in vitro studies, PDT, combined with targeted therapies and/or chemotherapy, could successfully target CSCs in different solid tumors and promote the reduction of stemness, suggesting a promising therapeutic approach requiring evaluation in robust pre-clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Purpose: To develop a radiomics-based hepatocellular carcinoma (HCC) grade classifier model based on data from gadoxetic acid-enhanced MRI., Methods: This retrospective study included 137 patients who underwent hepatectomy for a single HCC and gadoxetic acid-enhanced MRI within 60 days before surgery. HCC grade was categorized as low or high (modified Edmondson-Steiner grade I-II vs. III-IV). We used the hepatobiliary phase (HBP), portal venous phase, T2-weighted image(T2WI), and T1-weighted image(T1WI). From the volume of interest in HCC, 833 radiomic features were extracted. Radiomic and clinical features were selected using a random forest regressor, and the classification model was trained and validated using a random forest classifier and tenfold stratified cross-validation. Eight models were developed using the radiomic features alone or by combining the radiomic and clinical features. Models were validated with internal enrolled data (internal validation) and a dataset (28 patients) at a separate institution (external validation). The area under the curve (AUC) of the validation results was compared using the DeLong test., Results: In internal and external validation, the HBP radiomics-only model showed the highest AUC (internal 0.80 ± 0.09, external 0.70 ± 0.09). In external validation, all models showed lower AUC than those for internal validation, while the T2WI and T1WI models failed to predict the HCC grade (AUC 0.30-0.58) in contrast to the internal validation results (AUC 0.67-0.78)., Conclusion: The radiomics-based machine learning model from gadoxetic acid-enhanced liver MRI could distinguish between low- and high-grade HCCs. The radiomics-only HBP model showed the best AUC among the eight models, good performance in internal validation, and fair performance in external validation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The rapid growth of oral cancer is a significant concern, especially in developing countries due to the advanced lifestyle and 5-year survival despite advanced multimodality of cancer care. The poor modality might be due to the detection of disease in the advanced stage. Early detection and development of novel therapies can improve oral cancer patient survival. The PI3K/AKT/mTOR and RAS-RAF-MEK-ERK are very extensively exploited pathways in oral cancer. These pathways are very critical in the progression of tumorigenesis in oral cancer. This review focuses on the association of Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways in terms of protein expression level, genetic mutation, and therapeutic intervention in oral cancer., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Today, pancreatic cancer (PC) is a major health problem in the United States. It remains a challenge to develop efficacious clinically useful PC therapies. New avenues, based on translational approaches and innovative validated biomarkers could be a preclinical option to evaluate PC drug candidates or drug combinations before clinical trials. Herein, we describe evaluation of combination therapies by incorporating a novel pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) with other FDA-approved cancer drugs that have been used in PC clinical trials. PAWI-2 is a potent inhibitor of drug-resistant PC cells that has been shown to selectively ameliorate human pancreatic cancer stem cells (i.e., hPCSCs, FGβ 3 cells). In the present study, we showed PAWI-2 produced therapeutic synergism with certain types of anti-cancer drugs. These drugs themselves oftentimes do not ameliorate PC cells (especially PCSCs) due to high levels of drug-resistance. PAWI-2 has the ability to rescue the potency of drugs (i.e., erlotinib, trametinib) and inhibit PC cell growth. Key molecular regulators of PAWI-2 could be used to predict synergistic/antagonistic effects between PAWI-2 and other anti-cancer drugs. Anti-cancer results showed potency could be quite accurately correlated to phosphorylation of optineurin (OPTN) in PC cells. Synergism/antagonism was also associated with inhibition of PCSC marker SOX2 that was observed in FGβ 3 cells. Synergism broadens the potential use of PAWI-2 as an adjunct chemotherapy in patients with PC that have developed resistance to first-line targeted therapies or chemotherapies.

Background: Platelets (PLT) play an essential functional role in cellular injury and liver regeneration following partial hepatectomy and orthotopic liver transplantation (OLT). Here, we investigated the association of postoperative PLT counts with short- and long-term outcomes in adult OLT recipients., Methods: Three hundred consecutive patients from our prospective OLT database were analyzed retrospectively (May 2010-November 2017). Ninety-day post-OLT complications were graded using the Clavien-Dindo (CD) classification and quantified by the comprehensive complication index (CCI). To determine the prognostic accuracy of PLT counts, the area under the receiver operating characteristic curve (AUROC) was calculated for major complications (CD ≥ 3b). Parametric and non-parametric tests were applied for subgroup analyses. Uni- and multivariable logistic regression analyses were performed to identify risk factors for major complications. Graft and patient survival were analyzed using the Kaplan-Meier method as well as uni- and multivariable Cox regression analyses., Results: Postoperative day 6 PLT counts < 70 × 10 9 /L (POD6-70) were identified as the best cutoff for predicting major complications (AUROC = 0.7; p < 0.001; Youden index 0.317). The stratification of patients into low- (n = 113) and high-PLT (n = 187) groups highlighted significant differences in major complications (CCI 68 ± 29 vs. 43 ± 28, p < 0.001); length of hospital and intensive care unit (ICU) stay (53 ± 43 vs. 31 ± 25, p < 0.001; 21 ± 29 vs. 7 ± 11, p < 0.001, respectively) and estimated procedural costs. POD6-70 was associated with inferior 5-year graft survival. Multivariable logistic regression analysis identified POD6-70 as an independent predictor of major complications (odds ratio 2.298, confidence intervals 1.179-4.478, p = 0.015)., Conclusion: In OLT patients, a PLT count on POD6 of less than 70 × 10 9 /L bears a prognostic significance warranting further investigations.

Purpose: Although there is controversy, some evidences proposed increased risk of post-transplant Pneumocystis carinii pneumonia (PCP) in patients receiving mammalian target of rapamycin (mTOR) inhibitors. This study aimed to examine the association between m-TOR inhibitors and the risk of developing PCP in solid organ transplant (SOT) recipients., Methods: A comprehensive search was performed to find the eligible studies that investigated the incidence of PCP in patients treated with mTOR inhibitors after SOT. Random effect model was applied for meta-analysis., Results: Combination of 15 effect sizes showed a significant positive association between mTOR inhibitor administration and the risk of PCP (OR = 1.90, 95%CIs = 1.44, 2.75). There was no heterogeneity between studies (I 2  = 3.5%). Subgroup analysis revealed increased risk of PCP after the first year of transplantation (P < 0.001)., Conclusion: In conclusion, administration of mTOR inhibitors is a potential risk factor for late-onset PCP after SOT. Targeted PCP prophylaxis based on recipients' risk factors rather universal prophylaxis may lessen the risk.

Background Both the development of kidney function in healthy children and autoregulation ability of kidney function in patients with asymmetric kidneys are important in clinical diagnosis and treatment of kidney-related diseases, but there are however only limited studies. This study aimed to investigate development of kidney function in normal children with healthy symmetric kidneys and autoregulation of the healthy kidney compensating the functional loss of a diseased one in children with asymmetric kidneys. Methods Two hundred thirty-seven children (156 male, 81 female) from 0 to 20y (average 4.6y ± 5.1) undergoing .sup.99mTc-MAG3 renography were included, comprising 134 with healthy symmetrically functioning kidneys and 103 with asymmetric kidneys. Clearance was calculated from kidney uptakes at 1-2 min. A developmental model between MAG3 clearance (CL) and patient age in normal group was identified (CL = 84.39Age.sup.0.395 ml/min, r = 0.957, p < 0.001). The clearance autoregulation rate in abnormal group with asymmetric kidneys was defined as the ratio of the measured MAG3 clearance and the normal value predicted from the renal developmental model of normal group. Results No significant difference of MAG3 clearance (p = 0.723) was found between independent abnormal group and normal group. The autoregulation rate of kidney clearance in abnormal group was 94.2% on average, and no significant differences were found between two age groups (p = 0.49), male and female (p = 0.39), and left kidney and right kidney (p = 0.92) but two different grades of asymmetric kidneys (p = 0.02). Conclusions The healthy kidney of two asymmetric kidneys can automatically regulate total kidney function up to 94% of two symmetric kidneys in normal children. Graphical abstract, Author(s): Xinhua Cao [sup.1] , Xiaoyin Xu [sup.2] , S. Ted Treves [sup.2] , Laura A. Drubach [sup.1] , Neha Kwatra [sup.1] , Min Zhang [sup.2] , Frederic H. Fahey [...]

As life expectancy among pediatric solid organ transplant recipients (SOTRs) improves, the risk of comorbid conditions such as malignancy post-transplantation has also increased. SOTRs are at elevated risks of post-transplantation lymphoproliferative disorders (PTLDs), and skin and solid cancers. PTLDs typically occur early following transplantation, while skin and solid cancers frequently arise in young adulthood (25-40 years). By 30 years following transplantation, 26-41% of pediatric SOTRs have developed cancer. Different risk factors exist for PTLD, and skin and solid cancers, which are modified by cumulative immunosuppression, infections, transplanted organ, and the underlying disease process associated with initial organ failure (e.g., kidney failure). Optimal cancer treatment strategies depend on the specific cancer type, stage, and patient comorbidities. Immunosuppression reduction may be beneficial for certain cancers but must be considered against the risks of acute and chronic rejection and allograft loss. Lifestyle counseling regarding smoking avoidance and sun protection, as well as human papillomavirus vaccination, is an important aspect of cancer prevention. Currently, no cancer screening guidelines exist specifically for pediatric SOTRs. Adult population screening guidelines have not been validated in transplant populations. Therefore, an individualized approach should be taken to cancer screening for pediatric SOTRs, accounting for other cancer risk factors., Author(s): Cal Robinson [sup.1] [sup.2] , Rahul Chanchlani [sup.3] [sup.4] [sup.5] , Abhijat Kitchlu [sup.6] Author Affiliations: (1) grid.42327.30, 0000 0004 0473 9646, Division of Paediatric Nephrology, Department of Paediatrics, [...]