Identification of environmental factors that promote intestinal inflammation.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.

Multiple infusions of ex vivo-expanded regulatory T cells promote CD163+ myeloid cells and kidney allograft survival in non-lymphodepleted non-human primates.

Clinical verification of adoptively transferred regulatory T cell (Treg) efficacy in transplantation remains challenging. Here, we examined the influence of autologous ex vivo-expanded polyclonal Tregs on kidney graft survival in a clinically relevant non-human primate model. Peripheral blood Tregs were isolated and expanded using artificial antigen presenting cells. Immunosuppression was comprised of tapered tacrolimus and CTLA4 immunoglobulin, in five animals each without or with Treg infusions. Escalating Treg doses were administered 6, 10, 13, 16, 20, 23, 27 and 30 days after transplant. Infused Tregs were monitored for Treg signature, anti-apoptotic (Bcl-2) and proliferation (Ki67) marker expression. Treg infusions prolonged median graft survival time significantly from 35 to 70 days. Treg marker (Ki67 and Bcl-2) expression by infused Tregs diminished after their infusion but remained comparable to that of circulating native Tregs. No major changes in circulating donor-reactive T cell responses or total Treg percentages, or in graft-infiltrating T cell subsets were observed with Treg infusion. However, Treg infusion was associated with significant increases in CD163 expression by circulating HLA-DR+ myeloid cells and elevated levels of circulating soluble CD163. Further, graft-infiltrating CD163+ cells were increased with Treg infusion. Thus, multiple Treg infusions were associated with M2-like myeloid cell enhancement that may mediate immunomodulatory, anti-inflammatory and graft reparative effects.

Comprehensive Genomic and Transcriptomic Analysis of Sclerosing Pneumocytoma.

Sclerosing pneumocytoma is a rare and distinct lung neoplasm whose histogenesis and molecular alterations are the subject of ongoing research. Our recent study revealed that AKT1 internal tandem duplications (ITD), point mutations, and short indels were present in almost all tested sclerosing pneumocytomas, suggesting that AKT1 mutations are a major driving oncogenic event in this tumor. Although the pathogenic role of AKT1 point mutations is well established, the significance of AKT1 ITD in oncogenesis remains largely unexplored. We conducted comprehensive genomic and transcriptomic analyses of sclerosing pneumocytoma to address this knowledge gap. RNA-sequencing data from 23 tumors and whole-exome sequencing data from 44 tumors were used to obtain insights into their genetic and transcriptomic profiles. Our analysis revealed a high degree of genetic and transcriptomic similarity between tumors carrying AKT1 ITD and those with AKT1 point mutations. Mutational signature analysis revealed COSMIC signatures 1 and 5 as the prevailing signatures of sclerosing pneumocytoma, associated with the spontaneous deamination of 5-methylcytosine and an unknown etiology, respectively. RNA-sequencing data analysis revealed that the sclerosing pneumocytoma gene expression profile is characterized by activation of the PI3K/AKT/mTOR pathway, which exhibits significant similarity between tumors harboring AKT1 ITD and those with AKT1 point mutations. Notably, an upregulation of SOX9, a transcription factor known for its involvement in fetal lung development, was observed in sclerosing pneumocytoma. Specifically, SOX9 expression was prominent in the round cell component, whereas it was relatively lower in the surface cell component of the tumor. To the best of our knowledge, this is the first comprehensive investigation of the genomic and transcriptomic characteristics of sclerosing pneumocytoma. Results of the present study provide insights into the molecular attributes of sclerosing pneumocytoma and a basis for future studies of this enigmatic tumor.

Stereoselective Synthesis of Polysubstituted Dihydropyrroles via 1,5-Addition and N-1,4-Addition Cascade.

An unprecedented 1,5-addition/N-1,4-addition cascade reaction is established via palladium hydride catalysis. A variety of polysubstituted dihydropyrrole skeletons are constructed in high yield and with exclusively >20 : 1 diastereoselectivity. An enantioselective protocol of this design is also developed to provide a novel access to enantioenriched dihydropyrroles.

Optimal treatment strategy and prognostic analysis of salvage liver transplantation for patients with early hepatocellular carcinoma recurrence after hepatectomy.

AIM: We aimed to investigate the prognostic factors for salvage liver transplant in patients with early hepatocellular carcinoma recurrence after hepatectomy. METHODS: This retrospective analysis included 53 patients who underwent salvage living-donor liver transplantation between January 2007 and January 2018. There were 24 and 29 patients in the early (recurrence ≤24 months after primary liver resection) and the late recurrence groups, respectively. RESULTS: In the multivariate Cox regression model, pre-liver transplant downstaging therapy, early recurrence (ER) after primary liver resection , and recurrence-to-liver-transplant ≥12 months were independent risks to predict recurrent hepatocellular carcinoma recurrence after salvage living-donor liver transplantation. Compared with the late recurrence group, the ER group showed lower disease-free survival rates (p < 0.001); however, the overall survival rates did not differ between the two groups (p = 0.355). The 1-, 3-, and 5-year disease-free survival rates were 83.3%, 70.6%, and 66.2%, and 96.0%, 91.6%, and 91.6% in the early and late recurrence groups, respectively. When stratified by recurrence-to-liver transplant time and pre-liver transplant downstaging therapy in the ER group, disease-free survival and overall survival rates were significantly different. CONCLUSION: ER after primary liver resection with advanced tumor status and a longer period of recurrence-to-liver-transplant (≥12 months) have a negative impact on salvage liver transplant. Our findings provide novel recommendations for treatment strategies and eligibility for salvage liver transplant candidates.

Liver Resection Criteria for Patients with Hepatocellular Carcinoma and Multiple Tumors Based on Total Tumor Volume.

BACKGROUND: In many Asian hepatocellular carcinoma (HCC) guidelines, resection is an option for multiple HCCs. It is difficult to compare small but multiple tumors vs. fewer large tumors in terms of the traditional tumor burden definition. We aimed to evaluate the role of liver resection for multiple HCCs and determine factors associated with survival benefits. METHODS: We reviewed 160 patients with multiple HCCs who underwent liver resection between July 2003 and December 2018. The risk factors for tumor recurrence were assessed using Cox proportional hazards modeling, and survival was analyzed using the Kaplan-Meier method. RESULTS: In all 160 patients, 133 (83.1%) exceeded the Milan criteria. Total tumor volume (TTV) > 275 cm3 and serum alpha-fetoprotein (AFP) level > 20 ng/mL were associated with disease-free survival. Patients beyond the Milan criteria were grouped into three risk categories: no risk (TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL, n = 39), one risk (either TTV > 275 cm3 or AFP > 20 ng/mL, n = 76), and two risks (TTV > 275 cm3 and AFP > 20 ng/mL, n = 18). No-risk group had comparable disease-free survival (p = 0.269) and overall survival (p = 0.215) to patients who met the Milan criteria. CONCLUSION: Patients with TTV ≤ 275 cm3 and AFP ≤ 20 ng/mL can have good outcomes even exceed the Milan criteria.

Umpolung Asymmetric 1,5-Conjugate Addition via Palladium Hydride Catalysis.

Electronically matched nucleophilic 1,6-conjugate addition has been well studied and widely applied in synthetic areas. In contrast, nucleophilic 1,5-conjugate addition represents an electronically forbidden process and is considered unfeasible. Here, we describe modular protocols for 1,5-conjugate addition reactions via palladium hydride catalysis. Both palladium and synergistic Pd/organocatalyst systems are developed to catalyze 1,5-conjugate reaction, followed by inter- or intramolecular [3+2] cyclization. A migratory 1,5-addition protocol is established to corroborate the feasibility of this umpolung concept. The 1,5-addition products are conveniently transformed into a series of privileged enantioenriched motifs, including polysubstituted tetrahydrofuran, dihydrofuran, cyclopropane, cyclobutane, azetidine, oxetane, thietane, spirocycle and bridged rings. Preliminary mechanistic studies corroborate the involvement of palladium hydride catalysis.

Quick preparation of ABO-incompatible living donor liver transplantation for acute liver failure.

Acute liver failure is life-threatening and has to be treated by liver transplantation urgently. When deceased donors or ABO-compatible living donors are not available, ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) becomes the only choice. How to prepare ABO-I LDLT urgently is an unsolved issue. A quick preparation regimen was designed, which was consisted of bortezomib (3.5 mg) injection to deplete plasma cells and plasma exchange to achieve isoagglutinin titer ≤ 1: 64 just prior to liver transplantation and followed by rituximab (375 mg/m2 ) on post-operative day 1 to deplete B-cells. Eight patients received this quick preparation regimen to undergo ABO-I LDLT for acute liver failure from 2012 to 2019. They aged between 50 and 60 years. The median MELD score was 39 with a range from 35 to 48. It took 4.75 ± 1.58 days to prepare such an urgent ABO-I LDLT. All the patients had successful liver transplantations, but one patient died of antibody-mediated rejection at post-operative month 6. The 3-month, 6-month, and 1-year graft/patient survival were 100%, 87.5%, and 75%, respectively. In conclusion, this quick preparation regimen can reduce isoagglutinin titers quickly and make timely ABO-I LDLT feasible for acute liver failure.

Sequencing on an imported case in China of COVID-19 Delta variant emerging from India in a cargo ship in Zhoushan, China.

A cluster of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections was found in a cargo ship under repair in Zhoushan, China. Twelve of 20 crew members were identified as SARS-CoV-2 positive. We analyzed four sequences and identified them all in the Delta branch emerging from India with 7-8 amino acid mutation sites in the spike protein.

Radical bromination-induced ipso cyclization-ortho cyclization sequence of N-hydroxylethyl-N-arylpropiolamides.

A facile procedure is reported for the synthesis of various 2-bromo-1-phenyl-5,6-dihydro-3H,7aH-benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-ones via a radical bromination-induced ipso cyclization-ortho cyclization sequence of N-arylpropiolamides in the presence of TBAB and oxone. The radical cyclization sequence involves a radical bromo α-addition into the alkyne, ipso-cyclization, and ortho-trapping of the spirocyclic intermediate.

Improving outcomes of liver resection for hepatocellular carcinoma associated with portal vein tumor thrombosis over the evolving eras of treatment.

BACKGROUND: The outcomes and management of hepatocellular carcinoma (HCC) have undergone several evolutionary changes. This study aimed to analyze the outcomes of patients who had undergone liver resection for HCC with portal vein tumor thrombosis (PVTT) in terms of the evolving era of treatment. MATERIALS AND METHODS: A retrospective analysis of 157 patients who had undergone liver resection for HCC associated with PVTT was performed. The outcomes and prognostic factors related to different eras were further examined. RESULTS: Overall, 129 (82.1%) patients encountered HCC recurrence after liver resection, and the median time of recurrence was 4.1 months. Maximum tumor size ≥ 5 cm and PVTT in the main portal trunk were identified as the major prognostic factors influencing HCC recurrence after liver resection. Although the recurrence-free survival had no statistical difference between the two eras, the overall survival of patients in the second era was significantly better than that of the patients in the first era (p = 0.004). The 1-, 2-, and 3-year overall survival rates of patients in the second era were 60.0%, 45.7%, and 35.8%, respectively, with a median survival time of 19.6 months. CONCLUSION: The outcomes of HCC associated with PVTT remain unsatisfactory because of a high incidence of tumor recurrence even after curative resection. Although the management and outcomes of patients with HCC and PVTT have greatly improved over the years, surgical resection remains an option to achieve a potential cure of HCC in well-selected patients.

Gene Expression Profile in Primary Tumor Is Associated with Brain-Tropism of Metastasis from Lung Adenocarcinoma.

Lung adenocarcinoma has a strong propensity to metastasize to the brain. The brain metastases are difficult to treat and can cause significant morbidity and mortality. Identifying patients with increased risk of developing brain metastasis can assist medical decision-making, facilitating a closer surveillance or justifying a preventive treatment. We analyzed 27 lung adenocarcinoma patients who received a primary lung tumor resection and developed metastases within 5 years after the surgery. Among these patients, 16 developed brain metastases and 11 developed non-brain metastases only. We performed targeted DNA sequencing, RNA sequencing and immunohistochemistry to characterize the difference between the primary tumors. We also compared our findings to the published data of brain-tropic and non-brain-tropic lung adenocarcinoma cell lines. The results demonstrated that the targeted tumor DNA sequencing did not reveal a significant difference between the groups, but the RNA sequencing identified 390 differentially expressed genes. A gene expression signature including CDKN2A could identify 100% of brain-metastasizing tumors with a 91% specificity. However, when compared to the differentially expressed genes between brain-tropic and non-brain-tropic lung cancer cell lines, a different set of genes was shared between the patient data and the cell line data, which include many genes implicated in the cancer-glia/neuron interaction. Our findings indicate that it is possible to identify lung adenocarcinoma patients at the highest risk for brain metastasis by analyzing the primary tumor. Further investigation is required to elucidate the mechanism behind these associations and to identify potential treatment targets.

Combined GM-CSF and G-CSF administration mobilizes CD4+ CD25hi Foxp3hi Treg in leukapheresis products of rhesus monkeys.

Early phase clinical trials are evaluating the feasibility, safety, and therapeutic potential of ex vivo expanded regulatory T cells (Treg) in transplantation. A limitation is the paucity of naturally occurring Treg numbers in peripheral blood. Hence, protracted ex vivo expansion is required to obtain sufficient Treg in order to meet target cell doses. Because cytokine administration has been used successfully to mobilize immune cells to the peripheral blood in experimental and clinical studies, we hypothesized that granulocyte macrophage-colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) administration would enhance Treg percentages in leukapheresis products of rhesus monkeys. Following combined GM-CSF and G-CSF administration, the incidence of Treg in peripheral blood and leukapheresis products was elevated significantly, where approximately 3.7 × 106 /kg CD4+ CD25hi Foxp3hi or 6.8 × 106 /kg CD4+ CD25hi CD127lo Treg can be collected from individual products. Mobilized Treg expressed a comparable repertoire of surface markers, chemokine receptors, and transcription factors to naïve monkey peripheral blood Treg. Furthermore, when expanded ex vivo, mobilized leukapheresis product and peripheral blood Treg exhibited similar ability to suppress autologous CD4+ and CD8+ T cell proliferation. These observations indicate that leukapheresis products from combined GM-CSF- and G-CSF-mobilized individuals are a comparatively rich source of Treg and may circumvent long-term ex vivo expansion required for therapeutic application.

AKT1 internal tandem duplications and point mutations are the genetic hallmarks of sclerosing pneumocytoma.

Sclerosing pneumocytoma is a unique benign neoplasm of the lungs. The molecular alterations in sclerosing pneumocytoma are not well understood. In a previous whole-exome sequencing study, recurrent AKT1 point mutation was observed in about half of the cases of sclerosing pneumocytoma. However, in the remaining half, cancer-related mutations have still not been identified. In this study, we first analyzed the raw sequence data from the previous whole-exome sequencing study (PRJNA297066 cohort). Using Genomon-ITDetector, a special software for detection of internal tandem duplications, we identified recurrent internal tandem duplications in the AKT1 gene in 22 of the 44 tumor samples (50%). All the cases positive for AKT1 internal tandem duplications lacked AKT1 point mutations. Next, we performed targeted next-generation sequencing in an independent cohort of sclerosing pneumocytoma from our hospital (VGH-TPE cohort), and again identified recurrent AKT1 internal tandem duplications in 20 of the 40 (50%) tumor samples analyzed. The internal tandem duplications resulted in duplications of 7 to 16 amino acids in a narrow region of the Pleckstrin homology domain of the AKT1 protein. This region contains the interaction interface between the Pleckstrin homology and kinase domains, which is known to play a critical role in the activation of the AKT1 protein. Moreover, we found that AKT1 internal tandem duplications were mutually exclusive of other forms of AKT1 mutations, including point mutations and short indels. Taking all forms of AKT1 mutations together, we detected AKT1 mutations in almost all the sclerosing pneumocytomas in our study (PRJNA297066 cohort: 41 out of 44 cases, 93%; VGH-TPE cohort: 40 out of 40 cases, 100%). Our results suggest that AKT1 mutation is the genetic hallmark of sclerosing pneumocytoma. These results would help in better understanding of the pathogenesis of sclerosing pneumocytoma.

Differential expression analysis of clear cell renal cell carcinomas in The Cancer Genome Atlas distinguishes an aggressive subset enriched with chromosomes 7 and 12 gains.

AIMS: The Cancer Genome Atlas (TCGA) provides an integrated resource for investigating the genetic, phenotypical and clinical characteristics of cancer. In this study, we aimed to define distinct subsets of clear cell renal cell carcinoma (ccRCC) through differential expression and principal component analyses. METHODS AND RESULTS: We used DESeq2 to examine the expression profiles of 472 cases in TCGA. After a process of segregation and regrouping, we compared the mutation and copy number variation landscapes to discern two major clusters: cluster 1, composed mainly of classic ccRCC, and cluster 2, which was associated with gains at chromosomes 7 and 12. Gene set enrichment analysis disclosed that cluster 2 tumours were enriched in genes involving epithelial-mesenchymal transition. Histologically, cluster 2 tumours frequently exhibited cell elongation or spindling. Patients with cluster 2 tumours or tumours harbouring chromosomes 7 or 12 gains had a significantly greater cumulative incidence of mortality. We then employed fluorescence in-situ hybridisation with probes against chromosomes 7 and 12 in a cohort of 119 cases of ccRCC from our institute for validation. Chromosomes 7 and 12 gains were associated with lower survival rates in both univariate and multivariate analyses. CONCLUSIONS: Our study demonstrates that genetic data obtained through appropriate molecular methodologies can be a useful adjunct to help predict prognosis. It also provides an example of exploring TCGA to extract meaningful information that can eventually contribute to precision medicine.

Ortho-Hydroxylative ipso-Cyclization of N-arylpropiolamide.

A facile protocol for the tunable synthesis of 10-hydroxy-1-azaspiro[4.5]deca-3,6,8-trien-2-ones and benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-ones is described. A tunable synthesis has been realized by the use of ZnBr2/oxone and tetra-n-butylammonium bromide (TBAB)/oxone. The reaction proceeds smoothly with high efficiency and a broad substrate scope. Mechanistic studies indicate that an N-protecting group-assisted ortho-trapping reaction is involved. In the transformation, the reaction undergoes α-addition, ipso-cyclization, and ortho-trapping of the resulting spirocyclic species.

Low-dose anti-hepatitis B immunoglobulin regimen as prophylaxis for hepatitis B recurrence after liver transplantation.

BACKGROUND: Combination of anti-hepatitis B immunoglobulin (HBIg) and antiviral nucleotide/nucleoside is the most common regimen for prophylaxis against hepatitis B virus (HBV) recurrence. However, what the optimal regimen is for HBIg administration remains subject to debate. METHODS: Two hundred and thirty-two HBV patients who had liver transplantation were included in this study. According to the decline rate of HBIg, the patients were divided into quick (group Q, n = 95) and slow decline groups (group S, n = 137). Quick HBIg decline was defined as anti-HBs titer <200 IU/mL at postoperative month (POM) 1, when 24 000 IU of HBIg was given perioperatively. HBV recurrence was defined as reappearance of hepatitis B surface antigen (HBsAg). RESULTS: After a mean (range) follow-up of 42.2 (24.1-76.8) months, the HBV recurrence rate was 12.1% for all 232 patients. The median (interquartile) HBIg titer was 96.2 (41.0-158.0) IU in group Q patients, compared to 418.0 (298.8-692.8) IU in group S patients at POM 1 (P < .001). For the patients in group Q, 18 patients (18.9%) had HBV recurrence; this was higher than the 10 (7.3%) patients in group S (P = .013). Multivariate analysis showed that quick HBIg decline and hepatocellular carcinoma recurrence were the risk factors for HBV recurrence. CONCLUSION: Perioperative low-dose HBIg and antiviral nucleotide/nucleoside can effectively prevent HBV recurrence in patients with slow HBIg decline. For patients with quick HBIg decline, the idealized HBIg and antiviral agent regimen should be adjusted to establish an effective regimen as prophylaxis against HBV recurrence.

Clinical relevance of oncologic prognostic factors in the decision-making of pre-hepatectomy chemotherapy for colorectal cancer hepatic metastasis: the priority of hepatectomy.

BACKGROUND: Although liver resection (LR) provides the best chance of long-term survival for patients with colorectal cancer (CRC) hepatic metastasis, concerns regarding chemotherapy before liver resection remain unresolved. METHODS: A retrospective review of patients who underwent curative LR for CRC hepatic metastasis between January 2008 and February 2016 was performed. Outcome relevance based on oncologic prognostic factors and chemotherapy prior to liver resection was assessed. RESULTS: Patients who had received pre-hepatectomy chemotherapy for CRC hepatic metastasis and delayed liver resection had a worse outcome in terms of CRC recurrence following liver resection. The hazard ratio (HR) of pre-hepatectomy chemotherapy in patients with minor oncologic prognostic factors was 1.55 (confidence interval, CI = 1.07-2.26, p = 0.021) for CRC recurrence after liver resection for hepatic metastasis, whereas the HR of pre-hepatectomy chemotherapy was 1.34 (CI = 0.99-1.81, p = 0.062) for CRC recurrence in patients with multiple oncologic prognostic factors. CONCLUSION: The administration of pre-hepatectomy chemotherapy and delaying liver resection seems not to be an optimal strategy to provide a clinical benefit for patients with CRC hepatic metastasis. Hence, liver resection should be attempted without delay at the initial detection of CRC hepatic metastasis whenever possible.

Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection.

BACKGROUND: Hepatocellular carcinoma recurrence following liver resection remains a great concern. The study aims to examine the chemopreventive effect of metformin in patients undergoing liver resection for hepatocellular carcinoma from a population-based study. METHODS: All patients registered as having hepatocellular carcinoma between January 1995 and December 2011 in a nationwide database were retrospectively analysed. Outcomes related to liver resection and the presence of diabetes mellitus were assessed. Prognosis in terms of the use of metformin was further explored, in which only patients in the long-term follow-up starting at 2 years were included for analysis. RESULTS: Patients with diabetes mellitus had a significantly poorer outcome than patients without diabetes mellitus. Among diabetes mellitus patients, metformin users had significantly better survival curves in both recurrence-free survival (P<.0001) and overall survival (P<.0001) after liver resection. The hazard ratio of metformin use in hepatocellular carcinoma patients with diabetes mellitus was 0.65 (P<.05, 95% CI=0.60-0.72) for hepatocellular carcinoma recurrence and 0.79 (P<.05, 95% CI=0.72-0.88) for overall survival after liver resection. The risk reduction in hepatocellular carcinoma recurrence after liver resection was significantly associated with a dose/duration dependent of accumulated metformin usage. CONCLUSION: Diabetes mellitus has an adverse effect on patients with hepatocellular carcinoma regardless of treatment modality. The use of metformin significantly reduces the risk of hepatocellular carcinoma recurrence and improves the overall outcome of patients after liver resection if patients survives the initial 2 years. Nonetheless, a prospective controlled study is recommended for validating the metformin use on preventing postoperative hepatocellular carcinoma recurrence.

Prognostic impact and risk factors of low body mass index in patients undergoing liver transplantation.

We aimed to investigate the effect of body mass index (BMI) on the overall survival rates and to identify the risk factors associated with adverse outcomes. A total of 381 adult-to-adult living donor liver transplantations performed were retrospectively analyzed. These patients were classified according to the BMI categories established by the World Health Organization: The underweight group (BMI<18.5 kg/m2 ) and the non-underweight group (BMI≥18.5 kg/m2 ). The underweight group had significantly worse outcomes, compared with that of the non-underweight group (5-year overall survival: 45.6% vs 74.6%, P<.001). Underweight patients with CD4/CD8 ratio <1.4 had a significant worse prognosis, compared with those with CD4/CD8 ratio ≥1.4. (The 1-, 3-, and 5-year overall patient survival rates in both groups were 71.0% vs 20%, 58.9% vs 0%, and 53.6% vs 0%, respectively, P=.002.) In the multivariate analysis, only CD4/CD8 ratio <1.4 was an independent poor prognostic factor (hazard ratio=7.063, 95% confidence interval=1.329-37.547, P=.022). CONCLUSIONS: Pre-operative CD4/CD8 ratio <1.4 is an independent poor prognostic indicator for underweight patients undergoing liver transplantation. Early intervention in replenishing the nutrient deficit and cautious use of immunosuppressive regimens are essential to prepare this high-risk population for a more successful liver transplantation.