Ex vivo liver resection and auto-transplantation as an alternative for the treatment of liver malignancies: Progress and challenges.

Hepatectomy is still the major curative treatment for patients with liver malignancies. However, it is still a big challenge to remove the tumors in the central posterior area, especially if their location involves the retrohepatic inferior vena cava and hepatic veins. Ex vivo liver resection and auto-transplantation (ELRA), a hybrid technique of the traditional liver resection and transplantation, has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation. Due to its technical difficulty, ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation. The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases, especially in the advanced alveolar echinococcosis. Recently, the application of ELRA for liver malignances has gained more attention. However, standardization of clinical practice norms and international consensus are still lacking. The prognostic impact in these oncologic patients also needs further evaluation. In this review, we summarized the principles and recent progresses on ELRA.

Gorilla optimization algorithm combining sine cosine and cauchy variations and its engineering applications.

To address the issues of lacking ability, loss of population diversity, and tendency to fall into the local extreme value in the later stage of optimization searching, resulting in slow convergence and lack of exploration ability of the artificial gorilla troops optimizer algorithm (AGTO), this paper proposes a gorilla search algorithm that integrates the positive cosine and Cauchy's variance (SCAGTO). Firstly, the population is initialized using the refractive reverse learning mechanism to increase species diversity. A positive cosine strategy and nonlinearly decreasing search and weight factors are introduced into the finder position update to coordinate the global and local optimization ability of the algorithm. The follower position is updated by introducing Cauchy variation to perturb the optimal solution, thereby improving the algorithm's ability to obtain the global optimal solution. The SCAGTO algorithm is evaluated using 30 classical test functions of Test Functions 2018 in terms of convergence speed, convergence accuracy, average absolute error, and other indexes, and two engineering design optimization problems, namely, the pressure vessel optimization design problem and the welded beam design problem, are introduced for verification. The experimental results demonstrate that the improved gorilla search algorithm significantly enhances convergence speed and optimization accuracy, and exhibits good robustness. The SCAGTO algorithm demonstrates certain solution advantages in optimizing the pressure vessel design problem and welded beam design problem, verifying the superior optimization ability and engineering practicality of the SCAGTO algorithm.

Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

Neuroanatomical and functional substrates of the hypomanic personality trait and its prediction on aggression

Hypomanic personality manifests a close link with several psychiatric disorders and its abnormality is a risk indicator for developing bipolar disorders. We systematically investigated the potential neuroanatomical and functional substrates underlying hypomanic personality trait (HPT) and its sub-dimensions (i.e., Social Vitality, Mood Volatility, and Excitement) combined with structural and functional imaging data as well as their corresponding brain networks in a large non-clinical sample across two studies (n = 464). Behaviorally, HPT, specifically Mood Volatility and Excitement, was positively associated with aggressive behaviors in both studies. Structurally, sex-specific morphological characteristics were further observed in the motor and top-down control networks especially for Mood Volatility, although HPT was generally positively associated with grey matter volumes (GMVs) in the prefrontal, temporal, visual, and limbic systems. Functionally, brain activations related to immediate or delayed losses were found to predict individual variability in HPT, specifically Social Vitality and Excitement, on the motor and prefrontal-parietal cortices. Topologically, connectome-based prediction model analysis further revealed the predictive role of individual-level morphological and resting-state functional connectivity on HPT and its sub-dimensions, although it did not reveal any links with general brain topological properties. GMVs in the temporal, limbic (e.g., amygdala), and visual cortices mediated the effects of HPT on behavioral aggression. These findings suggest that the imbalance between motor and control circuits may be critical for HPT and provide novel insights into the neuroanatomical, functional, and topological mechanisms underlying the specific temperament and its impacts on aggression. (AU)

Clinical efficacy and safety of subcutaneous rituximab in non-Hodgkin lymphoma: a systematic literature review and meta-analysis.

OBJECTIVES: The role of subcutaneous (SC) rituximab in the efficacy and safety to non-Hodgkin lymphoma (NHL) is not clear enough. The purpose of this study was to conduct a systematic review and meta-analysis, to assess the efficacy and safety of subcutaneous rituximab to NHL. METHOD: A full-scale search was carried out based on the set search terms in PubMed, Web of Science, Embase and Cochrane CENTRAL until 12 October 2022 to identify relevant studies of subcutaneous rituximab for NHL. The efficacy and safety outcomes included complete response (CR) plus unconfirmed complete response (CRu), adverse events (AEs), grade ≥3 AEs, serious adverse events (SAEs), administration-related reactions (ARRs), adverse reaction rates. RESULTS: From a total of 758 studies, 9 trials were eligible. The CR/CRu of patients with NHL receiving SC rituximab was 57%, 55% for Diffuse large B-cell lymphoma (DLBCL) and 54% for Follicular lymphoma (FL). The meta-analysis performed on safety demonstrated that AEs of NHL patients with SC rituximab was 85%, grade ≥3 AEs was 38%, SAE was 27% and ARR was 33%. The result also showed that SC rituximab had a high risk of neutropenia and nausea. CONCLUSION: For NHL patients, there is no significant difference in the efficacy between subcutaneous rituximab and conventional therapy, while subcutaneous injection can shorten exposure time in the hospital and reduce the risk of infection.

Development and validation of a mutation-annotated prognostic score for intrahepatic cholangiocarcinoma after resection: a retrospective cohort study.

BACKGROUND: The value of existing prognostic models for intrahepatic cholangiocarcinoma is limited. The inclusion of prognostic gene mutations would enhance the predictive efficacy. METHODS: In the screening cohorts, univariable Cox regression analysis was applied to investigate the effect of individual mutant genes on overall survival (OS). In the training set, multivariable analysis was performed to evaluate the independent prognostic roles of the clinicopathological and mutational parameters, and a prognostic model was constructed. Internal and external validations were conducted to evaluate the performance of this model. RESULTS: Among the recurrent mutations, only TP53 and KRASG12 were significantly associated with OS across all three screening cohorts. In the training cohort, TP53 and KRASG12 mutations in combination with seven other clinical parameters (tumor size, tumor number, vascular invasion, lymph node metastasis, adjacent invasion, CA19-9, and CEA), were independent prognostic factors for OS. A mutation-annotated prognostic score (MAPS) was established based on the nine prognosticators. The C-indices of MAPS (0.782 and 0.731 in the internal and external validation cohorts, respectively) were statistically higher than those of other existing models ( P <0.05). Furthermore, the MAPS model also demonstrated significant value in predicting the possible benefits of upfront surgery and adjuvant therapy. CONCLUSIONS: The MAPS model demonstrated good performance in predicting the OS of intrahepatic cholangiocarcinoma patients. It may also help predict the possible benefits of upfront surgery and adjuvant therapy.

Neuroanatomical and functional substrates of the hypomanic personality trait and its prediction on aggression.

Hypomanic personality manifests a close link with several psychiatric disorders and its abnormality is a risk indicator for developing bipolar disorders. We systematically investigated the potential neuroanatomical and functional substrates underlying hypomanic personality trait (HPT) and its sub-dimensions (i.e., Social Vitality, Mood Volatility, and Excitement) combined with structural and functional imaging data as well as their corresponding brain networks in a large non-clinical sample across two studies (n = 464). Behaviorally, HPT, specifically Mood Volatility and Excitement, was positively associated with aggressive behaviors in both studies. Structurally, sex-specific morphological characteristics were further observed in the motor and top-down control networks especially for Mood Volatility, although HPT was generally positively associated with grey matter volumes (GMVs) in the prefrontal, temporal, visual, and limbic systems. Functionally, brain activations related to immediate or delayed losses were found to predict individual variability in HPT, specifically Social Vitality and Excitement, on the motor and prefrontal-parietal cortices. Topologically, connectome-based prediction model analysis further revealed the predictive role of individual-level morphological and resting-state functional connectivity on HPT and its sub-dimensions, although it did not reveal any links with general brain topological properties. GMVs in the temporal, limbic (e.g., amygdala), and visual cortices mediated the effects of HPT on behavioral aggression. These findings suggest that the imbalance between motor and control circuits may be critical for HPT and provide novel insights into the neuroanatomical, functional, and topological mechanisms underlying the specific temperament and its impacts on aggression.

Early Circulating Tumor DNA Dynamics Predict Neoadjuvant Therapy Response and Recurrence in Colorectal Liver Metastases: A Prospective Study.

BACKGROUND: For patients with colorectal liver metastases (CRLM) who receive neoadjuvant therapy (NAT), reliable indicators that can early and accurately predict treatment response are lacking. This study was conducted to prospectively investigate the potential of early circulating tumor DNA (ctDNA) dynamics as a precise predictor of NAT response and recurrence in CRLM. METHODS: This study prospectively enrolled 34 patients with CRLM who received NAT, with blood samples collected and subjected to deep targeted panel sequencing at two time points: 1 day before the first and the second cycles of NAT. Correlations of ctDNA mean variant allele frequency (mVAF) dynamics and treatment response were assessed. The performance of early ctDNA dynamics in predicting treatment response was assessed and compared with those of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). RESULTS: The baseline ctDNA mVAF was significantly associated with pre-NAT tumor diameter (r = 0.65; P < 0.0001). After one cycle of NAT, the ctDNA mVAF declined remarkably (P < 0.0001). The dynamic change in ctDNA mVAF of 50% or more was significantly correlated with better NAT responses. The discriminatory capacity of ctDNA mVAF changes was superior to that of CEA or CA19-9 in predicting radiologic response (area under the curve [AUC], 0.90 vs 0.71 vs 0.61) and pathologic tumor regression grade (AUC, 0.83 vs 0.64 vs 0.67). The early changes in ctDNA mVAF but not CEA or CA19-9 were an independent indicator of recurrence-free survival (RFS) (hazard ratio, 4.0; P = 0.023). CONCLUSIONS: For CRLM patients receiving NAT, an early ctDNA change is a superior predictor of treatment response and recurrence compared with conventional tumor markers.

Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy.

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function of IRG1/ITA has been established in multiple pathogen models, but very little is known in cancer. Here, we show that IRG1 is expressed in tumor-associated macrophages (TAMs) in both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression in macrophages by activating NF-κB pathway, and ITA produced by ACOD1 inhibits TET DNA dioxygenases to dampen the expression of inflammatory genes and the infiltration of CD8+ T cells into tumor sites. Deletion of Irg1 in mice suppresses the growth of multiple tumor types and enhances the efficacy of anti-PD-(L)1 immunotherapy. Our study provides a proof of concept that ACOD1 is a potential target for immune-oncology drugs and IRG1-deficient macrophages represent a potent cell therapy strategy for cancer treatment even in pancreatic tumors that are resistant to T cell-based immunotherapy.

Efficacy and safety of cyclosporine-based regimens for primary immune thrombocytopenia: a systematic review and meta-analysis.

OBJECTIVE: To conduct a meta-analysis assessing the efficacy and safety of cyclosporine-based combinations for primary immune thrombocytopenia (ITP). METHODS: Randomized controlled clinical trials were collected by systematically searching databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to June 2022. All studies included patients with ITP who received cyclosporine-based regimens. We performed comprehensive analyses of the overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, relapse rate, platelet count, and adverse drug reaction (ADR) rate. RESULTS: Seven studies (n = 418) were ultimately included. According to a fixed-effects model, cyclosporine-based combinations improved the ORR and CR rate and reduced the relapse rate. The ADR rate was not increased in the cyclosporine-based combination group. Cyclosporine-based regimens effectively increased the platelet count. Subgroup analysis illustrated that cyclosporine-based combinations were linked to higher ORRs in both children (odds ratio [OR] = 5.74, 95% confidence interval [CI] = 1.79-18.41) and adults (OR = 5.46, 95% CI = 2.48-12.02) and a higher CR rate in adults (OR = 2.97, 95% CI = 1.56-5.63). CONCLUSION: Cyclosporine exhibited efficacy in the treatment of ITP without increasing the risk of ADRs.

Greed personality trait links to negative psychopathology and underlying neural substrates.

Greed personality trait (GPT), characterized by the desire to acquire more and the dissatisfaction of never having enough, has been hypothesized to link with negative emotion/affect characteristics and aggressive behaviors. To describe its emotion-related features, we utilized a series of scales to measure corresponding emotion/affect and aggression (n = 411) and collected their neuroimaging data (n = 330) to explore underlying morphological substrates. Correlational analyses revealed that greedy individuals show more negative symptoms (e.g. depression, loss of interest, negative affect), lower psychological well-being and more aggression. Mediation analyses further demonstrated that negative symptoms and psychological well-being mediated greedy individuals' aggression. Moreover, exploratory factor analysis extracted factor scores across three factors (negative psychopathology, happiness, and motivation) from the measures scales. Negative psychopathology and happiness remained robust mediators. Importantly, these findings were replicated in an independent sample (n = 68). Voxel-based morphometry analysis also revealed that gray matter volumes (GMVs) in the prefrontal-parietal-occipital system were associated with negative psychopathology and happiness, and GMVs in the frontal pole and middle frontal cortex mediated the relationships between GPT and aggressions. These findings provide novel insights into the negative characteristics of dispositional greed, and suggest their mediating roles on greedy individuals' aggression and underlying neuroanatomical substrates.

Neurobiological substrates of the dread of future losses.

When anticipating future losses, people respond by exhibiting 1 of 2 starkly distinct behavioral decision patterns: the dread of future losses (DFL) and the preference of future losses (vs. immediate losses). Yet, how to accurately discriminate between those who exhibit dread vs. preference and uncover the potential neurobiological substrates underlying these 2 groups remain understudied. To address this, we designed a novel experimental task in which the DFL group was defined as selecting immediate-loss options >50% in the trials with approximate subjective value in immediate and delayed options (n = 16), otherwise coding as the preference of future losses (PFL). At the behavioral level, DFL exhibited higher weight for delayed losses than immediate losses via the logistic regression model. At the neural level, DFL manifested hypoactivations on subjective valuations of delayed losses, atypical brain pattern when choosing immediate-loss options, and decreased functional coupling between the valuation and choice-systems when making decisions related to immediate-loss alternatives compared with PFL. Moreover, both these brain activations subserving distinct decision processes and their interactions predicted individual decisions and behavioral preferences. Furthermore, morphological analysis also revealed decreased right precuneus volume in DFL compared with PFL, and brain activations related to valuation and choice process mediated the associations between this region volume and behavioral performances. Taken together, these findings help to clarify potential cognitive and neural mechanisms underlying the DFL and provide a clear discrimination strategy.

AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation.

BACKGROUND: Oxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver. METHODS: Orthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments. RESULTS: Compared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis. CONCLUSIONS: AADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM.

Effect of thrombopoietin receptor agonist on health-related quality of life and platelet transfusion burden for patients with myelodysplastic syndromes: a systematic review and meta-analysis.

Thrombocytopenia is a common and unsolved problem in myelodysplastic syndrome (MDS) patients; we aimed to summarize the evidence of TPO-RA treatment for heath-related quality of life (HRQoL) and platelet transfusion burden of MDS patients. We searched Pubmed, Web of Science, EMBASE, and CENTRAL for randomized clinical trials (RCTs) comparing TPO-RA to placebo in MDS published until July 31, 2021. A random-effect model was used. Eight RCTs with 908 patients were identified. Only three RCTs involving eltrombopag reported HRQoL, and all three studies treated HRQoL as a secondary outcome. In these three RCTs, the HRQoL instruments used in each study were different. However, this outcome cannot be meta-analyzed because some studies did not provide complete data. Subsequent clinical trials should pay more attention to this. Compared to placebo, TPO-RA did not affect platelet transfusion incidence 0.83 (95% CI 0.60-1.15). There was no evidence for subgroup differences in the analyses of different types of TPO-RA, different additional agent, and different types of MDS risk groups. However, platelet transfusion units (RR = 0.68, 95% CI 0.53 to 0.84) were significantly decreased. The RR of patients who did not require platelet transfusion for 56 or more consecutive days was not different between groups (RR = 0.98, 95% CI 0.41 to 2.34). TPO-RA may decrease platelet transfusion units in MDS patients with thrombocytopenia. But the significance of this finding should be interpreted with caution, because too few studies were meta-analyzed.

Metformin Inhibits HaCaT Cell Proliferation Under Hyperlipidemia Through Reducing Reactive Oxygen Species via FOXO3 Activation.

Purpose: Metformin (MET) has been proved to be effective for the treatment of psoriasis. The mechanisms of its action under the hyperlipidemia have yet to be fully elucidated. Here, we investigated the effect of metformin on the cell proliferation induced by hyperlipidemia and the underlying mechanism in immortalized human keratinocyte cell line (HaCat). Methods: Wild-type or FOXO3 knockdown HaCat cells were treated with free fatty acids (FFA) for 10 days and then co-treated with metformin for another 4 days. Triglyceride (TG) level, cell viability, proliferation, apoptosis, antioxidant enzymes, reactive oxygen species (ROS) levels, as well as the transcription activity of FOXO3 were analyzed. Results: Metformin decreased HaCaT cell proliferation and induced cell apoptosis after FFA treatment. Metformin was found to significantly increase the expressions and the activities of superoxide dismutase (SOD) as well as catalase (CAT), and reduced the reactive oxygen species (ROS) level. Metformin significantly promoted the autophagy and increase FOXO3 protein level in the nucleus under hyperlipidemia. However, all of the effects from metformin were partially blocked by FOXO3 knockdown. Conclusion: This study demonstrated that under the hyperlipidemia, metformin has significant antiproliferation and proapoptosis effects by reducing ROS level as well as increasing autophagy. All of these effects from metformin were through FOXO3-dependent pathway.

A polygenic stacking classifier revealed the complicated platelet transcriptomic landscape of adult immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease with the typical symptom of a low platelet count in blood. ITP demonstrated age and sex biases in both occurrences and prognosis, and adult ITP was mainly induced by the living environments. The current diagnosis guideline lacks the integration of molecular heterogenicity. This study recruited the largest cohort of platelet transcriptome samples. A comprehensive procedure of feature selection, feature engineering, and stacking classification was carried out to detect the ITP biomarkers using RNA sequencing (RNA-seq) transcriptomes. The 40 detected biomarkers were loaded to train the final ITP detection model, with an overall accuracy 0.974. The biomarkers suggested that ITP onset may be associated with various transcribed components, including protein-coding genes, long intergenic non-coding RNA (lincRNA) genes, and pseudogenes with apparent transcriptions. The delivered ITP detection model may also be utilized as a complementary ITP diagnosis tool. The code and the example dataset is freely available on http://www.healthinformaticslab.org/supp/resources.php.