Immune cell patterns before and after neoadjuvant immune checkpoint blockade combined with chemoradiotherapy in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant immune checkpoint blockade (ICB) combined with chemoradiotherapy offers high pathologic complete response (pCR) rate for patients with locally advanced esophageal squamous cell carcinomas (ESCC). But the dynamic tumor immune microenvironment modulated by such neoadjuvant therapy remains unclear. PATIENTS AND METHODS: A total of 41 patients with locally advanced ESCC were recruited. All patients received neoadjuvant toripalimab combined with concurrent chemoradiotherapy. Matched pre- and post-treatment tissues were obtained for fluorescent multiplex immunohistochemistry (mIHC) and IHC analyses. The densities and spatial distributions of immune cells were determined by HALO modules. The differences of immune cell patterns before and after neoadjuvant treatment were investigated. RESULTS: In the pre-treatment tissues, more stromal CD3 + FoxP3 + Tregs and CD86+/CD163 + macrophages were observed in patients with residual tumor existed in the resected lymph nodes (pN1), compared with patients with pCR. The majority of macrophages were distributed in close proximity to tumor nest in pN1 patients. In the post-treatment tissues, pCR patients had less CD86 + cell infiltration, whereas higher CD86 + cell density was significantly associated with higher tumor regression grades (TRG) in non-pCR patients. When comparing the paired pre- and post-treatment samples, heterogeneous therapy-associated immune cell patterns were found. Upon to the treatment, CD3 + T lymphocytes were slightly increased in pCR patients, but markedly decreased in non-pCR patients. In contrast, a noticeable increase and a less obvious decrease of CD86 + cell infiltration were respectively depicted in non-pCR and pCR patients. Furthermore, opposite trends of the treatment-induced alterations of CD8 + and CD15 + cell infiltrations were observed between pN0 and pN1 patients. CONCLUSIONS: Collectively, our data demonstrate a comprehensive picture of tumor immune landscape before and after neoadjuvant ICB combined with chemoradiotherapy in ESCC. The infiltration of CD86 + macrophage may serve as an unfavorable indicator for neoadjuvant toripalimab combined with chemoradiotherapy.

Analysing food groups and nutrient intake in adults who met and did not meet the daily recommended vegetable intake of 350 g: the 2016 National Health and Nutrition Survey in Japan.

This study aimed to compare the differences in the intake of food groups and nutrients between Japanese adults who consumed the recommended daily vegetable intake (350 g/day) and those who did not. Dietary information was obtained from one-day dietary records collected from the 2016 National Health and Nutrition Survey, which was conducted in 46 prefectures in Japan. The participants aged ≥20 years (n = 21,606; 53.8% women) were classified into the < and ≥350 g/day groups. Inter-group differences for 17 food groups and 27 nutrients were assessed as percentages of consumers (food groups only) and energy-adjusted intake (units/MJ/d or % of total energy intake). Overall, 29% of participants consumed ≥350 g/day of vegetables. The ≥350 g/day group had a higher percentage of consumers and energy-adjusted intakes for all vegetable subgroups than the <350 g/day group. For other food groups, the ≥350 g/day group had higher percentages of consumers for all food groups, except for cereals, eggs, and condiments and seasonings, which showed no significant differences. However, the ≥350 g/day group had a significantly higher energy-adjusted intake for potatoes and other tubers, mushrooms, meats, and condiments and seasonings but a significantly lower value for cereals, eggs, savoury snacks and confectionaries, and beverages. The ≥350 g/day group had a significantly higher intake of almost all (25/27) nutrients, including sodium, than the <350 g/day group. Participants with vegetable intake ≥350 g/day might have a more favourable intake of food groups and nutrients; however, watching for salt intake is necessary when promoting vegetable intake.

Transcriptional Responses of Different Brain Cell Types to Oxygen Decline.

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia.

Pan-Cancer Proteomics Analysis Reveals Wiskott-Aldrich Syndrome Protein as a Potential Regulator of Programmed Death-Ligand 1.

The programmed death-ligand 1 (PD-L1) is a key mediator of immunosuppression in the tumor microenvironment. The expression of PD-L1 in cancer cells is useful for the clinical determination of an immune checkpoint blockade (ICB). However, the regulatory mechanism of the PD-L1 abundance remains incompletely understood. Here, we integrated the proteomics of 52 patients with solid tumors and examined immune cell infiltration to reveal PD-L1-related regulatory modules. Wiskott-Aldrich syndrome protein (WASP) was identified as a potential regulator of PD-L1 transcription. In two independent cohorts containing 164 cancer patients, WASP expression was significantly associated with PD-L1. High WASP expression contributed to immunosuppressive cell composition, including cells positive for immune checkpoints (PD1, CTLA4, TIGIT, and TIM3), FoxP3+ Treg cells, and CD163+ tumor-associated macrophages. Overexpression of WASP increased, whereas knockdown of WASP decreased the protein level of PD-L1 in cancer cells without alteration of PD-L1 protein stability. The WASP-mediated cell migration and invasion were markedly attenuated by the silence of PD-L1. Collectively, our data suggest that WASP is a potential regulator of PD-L1 and the WASP/PD-L1 axis is responsible for cell migration and an immunosuppressive microenvironment.

Transurethral surgical treatment for benign prostatic hyperplasia with detrusor underactivity: a systematic review and meta-analysis.

BACKGROUND: The efficacy of surgical treatment for benign prostatic hyperplasia (BPH) patients with detrusor underactivity (DU) remains controversial. METHODS: To summarize relevant evidence, three databases (PubMed, Embase, and Web of Science) were searched from database inception to May 1, 2023. Transurethral surgical treatment modalities include transurethral prostatectomy (TURP), photoselective vaporization of the prostate (PVP), and transurethral incision of the prostate (TUIP). The efficacy of the transurethral surgical treatment was assessed according to maximal flow rate on uroflowmetry (Qmax), International Prostate Symptom Score (IPSS), postvoid residual (PVR), quality of life (QoL), voided volume, bladder contractility index (BCI) and maximal detrusor pressure at maximal flow rate (PdetQmax). Pooled mean differences (MDs) were used as summary statistics for comparison. The quality of enrolled studies was evaluated by using the Newcastle-Ottawa Scale. Sensitivity analysis and funnel plots were applied to assess possible biases. RESULTS: In this study, 10 studies with a total of 1142 patients enrolled. In BPH patients with DU, within half a year, significant improvements in Qmax (pooled MD, 4.79; 95% CI, 2.43-7.16; P < 0.05), IPSS(pooled MD, - 14.29; 95%CI, - 16.67-11.90; P < 0.05), QoL (pooled MD, - 1.57; 95% CI, - 2.37-0.78; P < 0.05), voided volume (pooled MD, 62.19; 95% CI, 17.91-106.48; P < 0.05), BCI (pooled MD, 23.59; 95% CI, 8.15-39.04; P < 0.05), and PdetQmax (pooled MD, 28.62; 95% CI, 6.72-50.52; P < 0.05) were observed after surgery. In addition, after more than 1 year, significant improvements were observed in Qmax (pooled MD, 6.75; 95%CI, 4.35-9.15; P < 0.05), IPSS(pooled MD, - 13.76; 95%CI, - 15.17-12.35; P < 0.05), PVR (pooled MD, - 179.78; 95%CI, - 185.12-174.44; P < 0.05), QoL (pooled MD, - 2.61; 95%CI, - 3.12-2.09; P < 0.05), and PdetQmax (pooled MD, 27.94; 95%CI, 11.70-44.19; P < 0.05). Compared with DU patients who did not receive surgery, DU patients who received surgery showed better improvement in PVR (pooled MD, 137.00; 95%CI, 6.90-267.10; P < 0.05) and PdetQmax (pooled MD, - 8.00; 95%CI, - 14.68-1.32; P < 0.05). CONCLUSIONS: Our meta-analysis results showed that transurethral surgery can improve the symptoms of BPH patients with DU. Surgery also showed advantages over pharmacological treatment for BPH patients with DU. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023415188.

The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome.

The human respiratory and circulatory systems collaborate intricately to ensure oxygen delivery to all cells, which is vital for ATP production and maintaining physiological functions and structures. During limited oxygen availability, hypoxia-inducible factors (HIFs) are stabilized and play a fundamental role in maintaining cellular processes for hypoxia adaptation. First discovered during investigations of erythropoietin production regulation, HIFs influence physiological and pathological processes, including development, inflammation, wound healing, and cancer. HIFs promote extracellular adenosine signaling by enhancing adenosine generation and receptor signaling, representing an endogenous feedback mechanism that curbs excessive inflammation, supports injury resolution, and enhances hypoxia tolerance. This is especially important for conditions that involve tissue hypoxia, such as acute respiratory distress syndrome (ARDS), which globally poses significant health challenges without specific treatment options. Consequently, pharmacological strategies to amplify HIF-mediated adenosine production and receptor signaling are of great importance.

[Corrigendum: How accurate are self-reported anthropometrics among the Japanese? A scoping review].

　Nihon Koshu Eisei Zasshi(JAPANESE JOURNAL OF PUBLIC HEALTH), Vol. 70 (2023) No. 12 pp.817-827.

A scoping review of dietary assessment questionnaires potentially suitable for assessing habitual dietary intake in the National Health and Nutrition Survey, Japan.

This scoping review aimed to identify questionnaire-based dietary assessment methods for use in the National Health and Nutrition Survey (NHNS) in Japan. The search was conducted in three databases (PubMed, Web of Science, and Ichushi) to identify questionnaire such as food frequency questionnaire and dietary history questionnaire validated against dietary recalls or food records for the intakes of both food groups and nutrients among Japanese adults. Study quality was assessed based on previously developed criteria. We extracted the questionnaire characteristics and the design and results of the validation studies. We identified 11 questionnaires, with the number of food items ranging from 40 to 196, from 32 articles of good quality. In the validation studies, participants were aged 30-76 years and 90% of the articles used ≥3 d dietary records as reference. The number of nutrients and food groups with a group-level intake difference within 20% against the reference method ranged from 1 to 30 and 1 to 11, respectively. The range of mean correlation coefficients between questionnaire and reference methods were 0.35-0.57 for nutrients and 0.28-0.52 for food groups. When selecting a survey instrument in the NHNS from the 11 existing questionnaires identified in this study, it is important to select one with high group-level comparison and correlation coefficient values on the intended assessment items after scrutinizing the design and results of the validation study. This review may serve as a reference for future studies that explore dietary assessment tools used for assessing dietary intake in specific representative populations.

Application of the zebrafish model in human viral research.

Viruses are a leading cause of infectious diseases. Well-developed animal models are valuable for understanding the immune responses to viral infections and the pathogenesis of viral diseases. Zebrafish is a commonly used small vertebrate model organism with strong reproductive ability, a short life cycle, and rapid embryonic development. Moreover, zebrafish and human genomes are highly similar; they have approximately 70 % homology in protein-coding genes, and 84 % of genes associated with human diseases have zebrafish counterparts. Recent years, different groups have developed zebrafish models for human viral infections and diseases, offering new insights into the molecular mechanisms of human viral pathogenesis as well as the development of antiviral strategies. The zebrafish model has become a simple and effective model system for understanding host-virus interaction. This review provides a comprehensive summary of the use of zebrafish models in human viral research, particularly in SARS-CoV-2.

Suffering and adjustment: a grounded theory of the process of coping with financial toxicity among young women with breast cancer.

PURPOSE: To explore the process of coping with financial toxicity among young women with breast cancer and formulate a grounded theory that serves as a foundation for creating intervention strategies aimed at supporting cancer survivors. METHODS: A qualitative study using the Corbin and Strauss variant of grounded theory. A series of in-depth interviews were carried out with young women with breast cancer (n = 29) using the theoretical sampling method. We analyzed data by coding core categories in the patients' coping processes and developing theory around these categories. Data collection and analysis were performed simultaneously. RESULTS: A substantial theory of the process of coping with financial toxicity among young female breast cancer survivors was constructed. Two core concepts, suffering and adjustment, were identified. Young women with breast cancer suffered from financial toxicity, which was related to risk factors, coping resources, and unmet needs. To overcome financial toxicity, young women with breast cancer adjusted by reshaping consumption concept, re-dividing of family functions, re-planning of occupation career, and rebuilding life confidence. CONCLUSION: This qualitative study constructed a theory delineating the coping strategies employed by young women with breast cancer in response to financial toxicity, offering profound insights into the intricacies of cancer-related financial toxicity. Identifying risk factors, enhancing coping resources, and meeting unmet needs would be helpful to patients' adjustment to financial stress.

Time Trends in Income-related Differences in Food Group Intakes: The National Health and Nutrition Survey, Japan in 2010, 2014, and 2018.

BACKGROUND: We aimed to clarify whether differences in food group intake according to household income have changed over the last decade in Japanese people aged 20 years or older. METHODS: This cross-sectional study was based on the 2010, 2014, and 2018 National Health and Nutrition Surveys in Japan. Food intake was assessed using a 1-day semi-weighed household dietary record. The participants were categorized into three groups based on their income. The mean of each food intake according to the income group was estimated by adjusting for age, occupation, and number of participants from the same household. The significance of the interaction terms between income and survey year was evaluated to assess the change in income-related differences in food intake over time. RESULTS: Cereal intake was lower in the middle- and the highest-income groups than in the lowest-income group, regardless of sex, and the interaction between income and year was nonsignificant for cereal intake. In the former two surveys, vegetable intake was higher among the highest-income women, while in the 2018 survey, the vegetable intake decreased in the women in the middle- and the highest-income groups. The interaction between income and year was significant for vegetable intake among the women. For other foods, the differences in intake among the income groups did not significantly change over time. CONCLUSION: The tendency for lower cereal intake in the higher-income groups was consistent over time in both the sexes, and the tendency for higher vegetable intake in the highest income women disappeared over time.

Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.

The association of highly processed food consumption with food choice values and food literacy in Japanese adults: a nationwide cross-sectional study.

BACKGROUND: Highly processed food (HPF) consumption is increasing globally and has become a prominent public health concern. However, the relationship between HPF consumption and food choice values and food literacy is unknown. This study aimed to examine the association of HPF consumption with food choice values and food literacy. METHODS: This cross-sectional study used data from a nationwide questionnaire survey conducted in 2018 among 2232 Japanese adults aged 18-80 years. We assessed eight food choice values (accessibility, convenience, health/weight control, tradition, sensory appeal, organic, comfort, and safety) using a 25-item scale, and food literacy characterised by nutrition knowledge (using a validated 143-item questionnaire), cooking and food skills (using 14- and 19-item scales, respectively), and eight eating behaviours (hunger, food responsiveness, emotional overeating, enjoyment of food, satiety responsiveness, emotional undereating, food fussiness, and slowness in eating, using the 35-item Adult Eating Behavior Questionnaire). HPF consumption was estimated using a validated brief diet history questionnaire. The associations between HPF consumption and age, body mass index, energy intake, and each score on food choice values and food literacy were evaluated by multiple linear regression. RESULTS: In males, one standard deviation increase in scores for cooking skill and satiety responsiveness was associated with an increase in HPF consumption by 22.1 g/4184 kJ (95% confidence interval (CI): 6.6 to 37.5) and 15.4 g/4184 kJ (95% CI: 6.0 to 24.7), respectively. In females, one standard deviation increase in age and scores for safety and nutrition knowledge corresponded to a decrease in HPF consumption by - 16.4 g/4184 kJ (95% CI: - 23.4 to - 9.3), - 9.9 g/4184 kJ (95% CI: - 19.1 to - 0.7), and - 11.1 g/4184 kJ (95% CI: - 17.0 to - 5.3), whereas one standard deviation increase in the satiety responsiveness score corresponded to an increase in HPF consumption by 13.1 g/4184 kJ (95% CI: 6.8 to 19.4). CONCLUSIONS: This cross-sectional study suggests that several aspects of food choice values and food literacy were associated with HPF consumption in Japanese adults. Further studies are needed to confirm our findings in a broader context.

Therapeutic targeting of hypoxia inducible factor in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by bilateral chest infiltration and acute hypoxic respiratory failure. ARDS carries significant morbidity and mortality despite advancements in medical management, calling for the development of novel therapeutic targets. Hypoxia-inducible factor (HIF) is a heterodimeric protein involved in various essential pathways, including metabolic reprogramming, immune modulation, angiogenesis and cell cycle regulation. HIF is routinely degraded in homeostasis conditions via the prolyl hydroxylase domain/von Hippel-Lindau protein pathway. However, HIF is stabilized in ARDS via various mechanisms (oxygen-dependent and independent) as an endogenous protective pathway and plays multifaceted roles in different cell populations. This review focuses on the functional role of HIF and its target genes during ARDS, as well as how HIF has evolved as a therapeutic target in current medical management.

[How accurate are self-reported anthropometrics among the Japanese? A scoping review].

Objectives　Monitoring of obesity and underweight prevalence in general populations is crucial for the implementation of effective public health measures. Self-reported height and weight values are often used to assess the body mass index (BMI) in such epidemiological surveillance. However, it is known that using self-reported height and weight may underestimate the prevalence of obesity (BMI≥25 kg/m2), while its accuracy for underweight (BMI<18.5 kg/m2) prevalence is not well-understood. The aim of this study was to conduct a scoping review on the accuracy of self-reported anthropometrics in the Japanese population, where both obesity and underweight are prevalent.Methods　Using PubMed and CiNii Research, a literature search was conducted for studies published in English or Japanese by 2022 that were conducted in Japan and compared self-reported and measured height, weight, or/and BMI. The study design and mean reported errors (mean of reported values－mean of measured values) were extracted and tabulated, and differences by BMI categories were also considered.Results　A total of 17 studies, with 11 being published in English, were included in this review. These studies were conducted in nationwide cohort studies (n=4), local populations (n=4), workplaces (n=3), and educational institutions (n=6), with diverse age ranges (10-91 years) and sample sizes (<100 to >30,000). Although the degree of mean reporting error varied between studies, most of the studies reported that height was overreported, weight was underreported, and BMI was underestimated. In the three studies that reported mean reporting errors by BMI category, the direction of reporting error for height remained consistent across all body size categories, while weight and BMI were overreported and overestimated only among the underweight. Four studies in adults showed that 14.2-37.6% of actually obese individuals and 11.1-32.3% of underweight individuals were misclassified as 'normal range' (18.5≤BMI<25 kg/m2) based on self-reporting, while 0.8-5.4% and 1.2-4.1% of individuals actually within the normal range were misclassified as 'underweight' and 'obese' based on self-report, respectively.Conclusion　This study suggests that using BMI based on self-reported height and weight can underestimate the prevalence of both obesity and underweight in the Japanese population. These biases should be taken into consideration when using self-reported anthropometrics in epidemiological studies.

Interventions for financial toxicity among cancer survivors: A scoping review.

INTRODUCTION: Financial toxicity impairs cancer survivors' material condition, psychological wellbeing and quality of life. This scoping review aimed to identify interventions for reducing cancer-related financial toxicity (FT), and to summarize their main findings. METHODS: A systematic search was performed in PubMed, Web of Science, EMBASE, CINAHL, Clinical Trials, China National Knowledge Internet, Wanfang and SinoMed from January 2010 to September 2022 following the PRISMA-ScR checklist. RESULTS: From 2842 identified articles, a total of 15 were included in this review. Existing interventions can be classified into four types: financial navigation, financial counseling, insurance education and others. Previous interventions preliminarily affirmed the feasibility, satisfaction, and improvement in financial worries and knowledge. However, the effectiveness on FT was controversial. CONCLUSIONS: Previous interventions affirmed the feasibility and primary effect of these interventions. Studies with more rigorous design are needed to evaluate the effectiveness and generalizability of interventions on FT across diverse healthcare systems.

Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans.

Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; CD66a), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of Ceacam1 affects ischemia-reperfusion injury (IRI) in mouse and human livers. We found that the short cytoplasmic isoform Ceacam1-S increased during early acute and late resolution phases of warm IRI injury in mice. Transfection of Ceacam1-deficient mouse hepatocytes with adenoviral Ceacam1-S mitigated hypoxia-induced loss of cellular adhesion by repressing the Ask1/p-p38 cell death pathway. Nucleic acid-blocking morpholinos, designed to selectively induce Ceacam1-S, protected hepatocyte cultures against temperature-induced stress in vitro. Luciferase and chromatin immunoprecipitation assays identified direct binding of hypoxia-inducible factor-1α (Hif-1α) to the mouse polypyrimidine tract binding protein 1 (Ptbp1) promoter region. Dimethyloxalylglycine protected mouse livers from warm IR stress and hepatocellular damage by inhibiting prolyl hydroxylase domain-containing protein 1 and promoting AS of Ceacam1-S. Last, analysis of 46 human donor liver grafts revealed that CEACAM1-S positively correlated with pretransplant HIF1A expression. This also correlated with better transplant outcomes, including reduced TIMP1, total bilirubin, proinflammatory MCP1, CXCL10 cytokines, immune activation markers IL17A, and incidence of delayed complications from biliary anastomosis. This translational study identified mouse Hif-1α-controlled AS of Ceacam1, through transcriptional regulation of Ptbp1 promoter region, as a functional underpinning of hepatoprotection against IR stress and tissue damage in liver transplantation.