Artificial intelligence/neural network system that accurately diagnoses hepatocellular carcinoma in nonalcoholic steatohepatitis.

BACKGROUND AND AIM: The aim of this study was to develop a novel noninvasive test using an artificial intelligence/neural network system (called HCC-Scope) to diagnose early-stage hepatocellular carcinoma (HCC) on the background of nonalcoholic steatohepatitis (NASH). METHODS: In total, 175 patients with histologically proven nonalcoholic fatty liver disease and 55 patients with NASH-HCC were enrolled for training and validation studies. Of the 55 patients with NASH-HCC, 27 (49.1%) had very early-stage HCC, and six (10.9%) had early-stage HCC based on the Barcelona Clinic Liver Cancer staging system. Diagnosis with HCC-Scope was performed based on 12 items: age, sex, height, weight, AST level, ALT level, gamma-glutamyl transferase level, cholesterol level, triglyceride level, platelet count, diabetes status, and IgM-free apoptosis inhibitor of macrophage level. The FMVWG2U47 hardware (Fujitsu Co. Ltd, Tokyo, Japan) and the originally developed software were used. RESULTS: HCC-Scope had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100% for the differential diagnosis between non-HCC and HCC in a training study with gray zone analysis. It was also excellent in the validation study (95.0% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV with gray zone analysis and 95.2% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV without gray zone analysis). HCC-Scope had a significantly higher sensitivity (85.3%) and specificity (85.1%) than alpha-fetoprotein (AFP) level, AFP-L3 level, des-gamma-carboxy prothrombin (DCP) level, and the gender-age-AFP-L3-AFP-DCP (GALAD) score. CONCLUSIONS: HCC-Scope can accurately differentially diagnose between non-HCC NASH and NASH-HCC, including very early-stage NASH-HCC.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Serum levels of immunoglobulin M-free inhibitors of macrophage/CD5L as a predictive and early diagnostic marker for nonalcoholic steatohepatitis-associated hepatocellular carcinoma.

BACKGROUND: The apoptosis inhibitor of macrophage (AIM) is usually associated with the immunoglobulin M (IgM) pentamer in the blood and is dissociated from IgM in various diseases, including hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH). We aimed to elucidate whether IgM-free AIM (fAIM) is useful for detecting latent HCC in NASH. METHODS: This research consisted of two cohort studies. The levels of serum fAIM, alpha-fetoprotein (AFP), and des-gamma carboxy prothrombin (DCP) of 18 NASH patients who developed HCC were measured during the follow-up period before HCC diagnosis (median, 4.7 years). In total, 199 patients with nonalcoholic fatty liver disease (NAFLD) were included in the HCC survey. The serum fAIM levels were analyzed using enzyme-linked immunosorbent assays. RESULTS: In the cohort of 18 patients with HCC, 12 had high fAIM at the time of the initial blood sample, three had normal fAIM levels throughout the follow-up period, and three had fAIM elevated from normal to positive. The positive ratio of fAIM prior to HCC diagnosis remained significantly higher than that of AFP and DCP, and the fAIM ratio gradually increased. In a survey of 199 non-HCC NAFLD patients, a Cox regression analysis using independent variables, such as AFP, fAIM, age, albumin, bilirubin, and fibrosis stage, revealed that fAIM and AFP were significantly associated with the incidence of HCC. CONCLUSIONS: During the development of NASH-HCC, AIM activation in blood appears to start even before HCC is diagnostically detectable. Thus, the serum IgM-free AIM levels could be a new, sensitive biomarker for latent NASH-HCC.

Hepatocellular carcinoma diagnosis using a novel electrochemiluminescence immunoassay targeting serum IgM-free AIM.

BACKGROUND: Recent increases in the number of patients with non-alcoholic steatohepatitis (NASH) warrant the identification of biomarkers for early detection of hepatocellular carcinoma (HCC) associated with NASH (NASH-HCC). IgM-free apoptosis inhibitor of macrophage (AIM), which generally associates with IgM in blood and exerts its biological function by dissociation from IgM, may serve as an effective biomarker for NASH-HCC. Here, we established a fully automatic and high-throughput electrochemiluminescence immunoassay (ECLIA) to measure IgM-free AIM and investigated its efficacy in diagnosing NASH-HCC and viral HCC. METHODS: IgM-free AIM levels were measured in 212 serum samples from patients with, or without, HCC related to NASH, hepatitis B virus, and hepatitis C virus, using ECLIA. We also developed an ECLIA for measuring both IgM-free and IgM-bound AIM and investigated the existing form of AIM in blood by size-exclusion chromatography. RESULTS: IgM-free AIM levels were significantly higher in the HCC group than in the non-HCC group, regardless of the associated pathogenesis. Moreover, the area under the receiver operating curve for IgM-free AIM was greater than that for conventional HCC biomarkers, alpha-fetoprotein or des-γ-carboxy prothrombin, regardless of the cancer stage. ECLIA counts of IgM-free AIM derived from samples fractionated by size-exclusion chromatography were significantly higher in patients with NASH-HCC than in healthy volunteers and in patients with non-alcoholic fatty liver and NASH. CONCLUSIONS: Serum IgM-free AIM may represent a universal HCC diagnostic marker superior to alpha-fetoprotein or des-γ-carboxy prothrombin. Our newly established ECLIA could contribute to further clinical studies on AIM and in vitro HCC diagnosis.

AIM/CD5L attenuates DAMPs in the injured brain and thereby ameliorates ischemic stroke.

The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.

Durable response after discontinuation of pembrolizumab therapy for intrahepatic cholangiocarcinoma: a case report.

Although it has recently been reported that immune checkpoint inhibitors (ICIs) constitute effective treatment for solid tumors, the success rate in patients with intrahepatic cholangiocarcinoma is limited. We administered pembrolizumab to a patient as treatment for liver and lymph node metastases of intrahepatic cholangiocarcinoma. The patient had abundant infiltration of programmed death ligand 1-positive macrophages, cytotoxic T cells (CD8-positive lymphocytes), and programmed death 1-positive lymphocytes as well as a high combined positive score of 33.1, high-frequency microsatellite instability, and mismatch repair deficiency. These characteristics are predictive biomarkers of the efficacy of ICIs. After pembrolizumab was administered four times (triweekly administration), the carbohydrate antigen 19-9 serum level fell within the normal range, and computed tomography revealed that the size of the metastatic liver tumors and enlarged hilar lymph node had markedly decreased. However, the patient developed pruritus and exanthema on the trunk and limbs after 14 administrations and was diagnosed with bullous pemphigoid. We discontinued pembrolizumab therapy and started treatment for bullous pemphigoid. Nine months after discontinuation of pembrolizumab therapy, the patient remains alive without tumor relapse. This patient had durable response even after discontinuation of pembrolizumab therapy for multiple metastases of intrahepatic cholangiocarcinoma.

IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development.

Among various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.

Precancerous Lesions and Liver Atrophy as Risk Factors for Hepatolithiasis-Related Death after Liver Resection for Hepatolithiasis.

BACKGROUND: Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis. METHODS: The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P. RESULTS: In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively. CONCLUSIONS: Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors.
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Impact of the Preoperative C-reactive Protein to Albumin Ratio on the Long-Term Outcomes of Hepatic Resection for Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The present study aimed to investigate the impact of preoperative C-reactive protein to albumin (CRP/Alb) ratio on the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC). METHODS: 82 patients who underwent hepatic resection for mass-forming type of ICC were evaluated. The relationship between preoperative CRP/Alb ratio and survival outcomes was investigated. RESULTS: The optimal cutoff value of CRP/Alb ratio for assessing overall survival (OS) was determined as 0.089. Univariate analysis for recurrence-free survival (RFS) showed that CRP/Alb ratio >0.089, carbohydrate antigen 19-9 (CA 19-9) >37 U/mL, lymph node metastasis, vascular invasion, and multiple tumors were significantly associated with postoperative recurrence. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.006), and multiple tumors (p < 0.001). Univariate analysis for OS showed that CRP/Alb ratio >0.089, CA 19-9 >37 U/mL, lymph node metastasis, vascular invasion, multiple tumors, and positive surgical margin were significantly associated with overall death. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.01), and multiple tumors (p = 0.005). CONCLUSION: Preoperative CRP/Alb ratio may predict poor long-term outcomes after hepatic resection in patients with ICC.
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Predictive Value of the Age-Adjusted Charlson Comorbidity Index for Outcomes After Hepatic Resection of Hepatocellular Carcinoma.

BACKGROUND: This study aimed to evaluate the impact of the age-adjusted Charlson comorbidity index (ACCI) on outcomes after hepatic resection for hepatocellular carcinoma (HCC). METHODS: We assessed 763 patients who underwent hepatic resection for HCC. The ACCI scores were categorized as follows: ACCI ≤ 5, ACCI = 6, and ACCI ≥ 7. RESULTS: A multivariate analysis showed that the odds ratios for postoperative complications in ACCI = 6 and ACCI ≥ 7 groups, with reference to ACCI ≤ 5 group, were 0.71 (p = 0.41) and 4.15 (p < 0.001), respectively. The hazard ratios for overall survival of ACCI = 6 and ACCI ≥ 7 groups, with reference to ACCI ≤ 5 group, were 1.52 (p = 0.023) and 2.45 (p < 0.001), respectively. The distribution of deaths due to HCC-related, liver-related, and other causes was 68.2%, 11.8%, and 20% in ACCI ≤ 5 group, 47.2%, 13.9%, and 38.9% in ACCI = 6 group, and 27.3%, 9.1%, and 63.6% in ACCI ≥ 7 group (p = 0.053; ACCI ≤ 5 vs. = 6, p = 0.19; ACCI = 6 vs. ≥ 7, p < 0.001; ACCI ≤ 5 vs. ≥ 7). In terms of the treatment for HCC recurrence in ACCI ≤ 5, ACCI = 6, and ACCI ≥ 7 groups, adaptation rate of surgical resection was 20.1%, 7.3%, and 11.1% and the rate of palliative therapy was 4.3%, 12.2%, and 22.2%, respectively. CONCLUSIONS: The ACCI predicted the short-term and long-term outcomes after hepatic resection of HCC. These findings will help physicians establish a treatment strategy for HCC patients with comorbidities.

Prognostic value of expanded liver transplantation criteria-the 5-5-500 rule-in patients with hepatic resection for intermediate-stage hepatocellular carcinoma.

BACKGROUND: This study aimed to evaluate the prognostic impact of the 5-5-500 rule in patients after hepatic resection for the intermediate stage of hepatocellular carcinoma (HCC; The Barcelona Clinic Liver Cancer classification [BCLC] B). METHODS: 177 patients had hepatic resection for BCLC-B HCC. The 5-5-500 rule was defined by tumor size ≤5 cm in diameter, tumor number ≤5, and α-fetoprotein ≤500 ng/mL. RESULTS: The 3-, 5-, and 7-year recurrence-free survival rates were 22%, 14%, and 11% in patients within the 5-5-500 rule, and 16%, 10%, and 10% in patients beyond the 5-5-500 rule, respectively (P = .015). The 3-, 5-, and 7-year overall survival rates were 72%, 47%, and 34% in patients within the 5-5-500 rule, and 52%, 31%, and 25% in patients beyond the 5-5-500 rule, respectively (P = .035). Being beyond the 5-5-500 rule and liver cirrhosis were independent prognostic factors for recurrence-free survival. For overall survival, being beyond the 5-5-500 rule, age ≥65 years, Child-Pugh class B, and anti-hepatitis C antibody positive were identified as independent prognostic factors. CONCLUSIONS: The 5-5-500 rule could predict prognosis in BCLC-B patients with hepatic resection. Hepatic resection might provide survival benefit for selected patients with BCLC-B HCC within the 5-5-500 rule.

Outcomes of Non-B Non-C Hepatocellular Carcinoma with Reference to Patients with Interferon-Induced Hepatitis C Virus Eradication.

PURPOSE: This study aimed to evaluate survival outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) with reference to patients with HCC achieving sustained virological response (SVR) by preoperative interferon (IFN) treatment for chronic hepatitis C. METHODS: We examined 781 patients who underwent hepatic resection for HCC. They were classified into NBNC-HCC, SVR-HCC, and non-SVR HCC groups. RESULTS: Multivariate analysis for recurrence-free survival (RFS) and overall survival (OS) revealed that the adjusted hazard ratios (HR) of NBNC-HCC and non-SVR HCC groups with reference to the SVR-HCC group were 1.46 (p = 0.10) and 2.10 (p < 0.001), respectively, for RFS, and 1.69 (p = 0.024) and 2.11 (p < 0.001), respectively, for OS. Worsening of Child-Pugh grade at recurrence was confirmed in 21 patients (17.1%) with NBNC-HCC but not in those with SVR-HCC (p = 0.017, SVR vs. NBNC). In the NBNC-HCC group, hepatic resection for intrahepatic recurrence was adopted in 17.4% of patients without worsening of Child-Pugh grade at recurrence, whereas hepatic resection was not adopted in those with grade worsening. Among patients with alcoholic hepatitis, Child-Pugh grade worsening at recurrence was more frequently observed in patients with sobriety than those without sobriety (14.3% vs. 46.2%, p = 0.049). CONCLUSIONS: NBNC-HCC patients had an increased risk for overall death as compared with those with SVR-HCC. Worsening of background liver function may reduce the chances of re-hepatic resection for recurrence and increase the risk for overall death in NBNC-HCC patients. For alcoholic hepatitis patients, sobriety may prevent deterioration of liver function after surgery.

Giving short-term prophylactic antibiotics in patients undergoing open and laparoscopic hepatic resection.

AIM: The 2016 guidelines of the Japan Society for Surgical Infection and the Japan Society of Chemotherapy advocate giving prophylactic antibiotics 1 hour before surgery and until 24 hours after surgery in patients undergoing elective hepatic resection. However, the efficacy of short-term antimicrobial prophylaxis has not been evaluated according to surgical approach. We evaluated the efficacy of giving prophylactic antibiotics in patients undergoing open or laparoscopic hepatic resection. METHODS: The study comprised 218 and 185 patients undergoing open and pure laparoscopic hepatic resection, respectively. Incidence rates of postoperative infectious complications were compared between patients who received flomoxef sodium as the prophylactic antibiotic before and until 24 hours after surgery (short-term group) and those who received flomoxef sodium until 72 hours after surgery (long-term group) among patients undergoing open or laparoscopic hepatic resection. Propensity score matching analysis was carried out to adjust for confounding factors between the short- and long-term groups. RESULTS: There was no significant difference in the postoperative infectious complication incidence between the short- and long-term groups among patients undergoing open (18.9% vs 12.2%; P = 0.36) or laparoscopic (3.3% vs 1.7%; P > 0.99) hepatic resection after propensity score matching. Incidence rate of surgical site infections was comparable between the short- and long-term groups among patients undergoing open (13.5% vs 10.8%; P = 0.80) or laparoscopic (3.3% vs 1.7%; P > 0.99) hepatic resection. CONCLUSION: Giving short-term prophylactic antibiotics might be sufficient in preventing postoperative infectious complications in patients undergoing open and laparoscopic hepatic resection.

AIM-deficient mouse fed a high-trans fat, high-cholesterol diet: a new animal model for nonalcoholic fatty liver disease.

Owing to changes in lifestyle, nonalcoholic fatty liver disease (NAFLD) is becoming a common form of chronic liver injury. NAFLD comprises a wide variety of disease stages, from simple steatosis to nonalcoholic steatohepatitis, which is a risk factor for the development of hepatocellular carcinoma (HCC). Because animal models for NAFLD are needed to investigate the precise pathogenesis, we aimed to establish a new mouse model employing mice deficient for apoptosis inhibitor of macrophage (AIM-/-), which exhibit accelerated lipid storage in the liver and high susceptibility to developing HCC in response to a high-fat diet (HFD). AIM-/- mice were fed the D09100301 diet, which contains 40 kcal% fat (trans fat 30 kcal%), high cholesterol (2%), and 40 kcal% carbohydrates (20 kcal% fructose), and then features of obesity and NAFLD including steatosis, inflammation, fibrosis, and HCC development were analyzed. Although a comparable grade of liver steatosis was promoted in AIM-/- mice by the D09100301 diet and the standard HFD (60 kcal% largely lard fat), significantly less lipid storage in visceral fat was observed when the mice were fed the D09100301 diet. Accelerated liver inflammation was promoted by the D09100301 diet compared with the HFD, but interestingly, HCC development was decreased in mice fed the D09100301 diet. Our findings suggest that AIM-/- mice fed the D09100301 diet exhibited a phenotype that resembled nonobese NAFLD patients and thus could be an appropriate tool to study the pathophysiology by which obesity increases the risk of HCC.

A scavenging system against internal pathogens promoted by the circulating protein apoptosis inhibitor of macrophage (AIM).

An internal system designed to ward off and remove unnecessary or hazardous materials is intrinsic to animals. In addition to exogenous pathogens, a number of self-molecules, such as apoptotic or necrotic dead cells, their debris, and the oxides or peroxides of their cellular components, are recognized as extraneous substances. It is essential to eliminate these internal pathogens as quickly as possible because their accumulation can cause chronic inflammation as well as autoimmune responses, possibly leading to onset or progression of certain diseases. Apoptosis inhibitor of macrophage (AIM, also called CD5L) is a circulating protein that is a member of the scavenger receptor cysteine-rich superfamily, and we recently found that during acute kidney injury, AIM associates with intraluminal dead cell debris accumulated in renal proximal tubules and enhances clearance of luminal obstructions, thereby facilitating repair. Thus, AIM acts as a marker for phagocytes so that they can efficiently recognize and engulf the debris as their targets. In this chapter, we give an overview of the professional and non-professional phagocytes, and how soluble scavenging molecules such as AIM contribute to improvement of diseases by stimulating phagocytic activity.

The IgM pentamer is an asymmetric pentagon with an open groove that binds the AIM protein.

Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.

Independent modes of disease repair by AIM protein distinguished in AIM-felinized mice.

Tissue macrophage-derived apoptosis inhibitor of macrophage (AIM, encoded by cd5l gene) is a circulating protein that has suppressive functions in a broad range of diseases including obesity, liver steatosis, hepatocellular carcinoma (HCC), and acute kidney injury (AKI). In healthy states, high levels of AIM circulate in the inactivated state by associating with the immunoglobulin M (IgM) pentamer in the blood, whereas during AKI, AIM dissociates from IgM and gains disease repair activity. Here, we assessed whether AIM activation via its release from IgM is required to ameliorate other diseases. To this end, we employed a mouse line in which mouse AIM was replaced with feline AIM (AIM-felinized mice). Because feline AIM rarely dissociates from IgM due to its extremely high binding affinity for IgM, these mice exhibited deficient AKI repair as in cats. When fed a high-fat diet (HFD), similar to AIM-deficient (AIM-/-) mice, AIM-felinized mice exhibited enhanced triacylglycerol deposition in visceral adipocytes and hepatocytes, resulting in more prominent obesity and fatty liver than in wild-type mice. In contrast, the incidence of HCC after a 1-year HFD was remarkably lower in AIM-felinized mice than in AIM-/- mice, suggesting that AIM produced by liver Kupffer macrophages might directly facilitate the elimination of HCC cells. Accordingly, the marked deposition of AIM accompanied by accumulation of Kupffer cells was obvious during HCC tumour development in AIM-felinized mice. Δsµ mice, which harbour almost no circulating AIM due to the lack of secreted IgM, showed a phenotype comparable with that of AIM-felinized mice in prevention of those diseases. Thus, blood AIM released from IgM contributes to suppression of obesity and fatty liver as in AKI, whereas macrophage-derived noncirculating AIM mainly prevents HCC development. Our study depicted two different modes of disease prevention/repair facilitated by AIM, which could be the basis for HCC therapy that works by increasing AIM expression in macrophages.

Obesity and recurrence-free survival in patients with hepatocellular carcinoma after achieving sustained virological response to interferon therapy for chronic hepatitis C.

AIM: Some patients who achieve a sustained virological response (SVR) to interferon (IFN) treatment for chronic hepatitis C prior to hepatic resection for hepatocellular carcinoma (HCC) experience postoperative recurrence. This study investigated the relationship between obesity and postoperative HCC recurrence in SVR patients. METHODS: Fifty-nine patients who had achieved SVR before hepatic resection were evaluated. Patients had a solitary tumor ≤5 cm in diameter or ≤3 lesions each ≤3 cm in size with no macroscopic vascular invasion (Milan criteria). Patient characteristics potentially associated with recurrence risk were investigated. RESULTS: Three-, 5-, and 7-year recurrence-free survival after surgery were 65%, 44%, and 41%, respectively. Univariate analysis showed that obesity (P < .01), hypertension (P = .038), and non-anatomical resection (P = .022) were significantly associated with a lower recurrence-free survival rate. In a multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval [CI] 1.3-6.1; P < .01) and non-anatomical resection (hazard ratio, 2.7; 95% CI 1.1-6.2; P = .025) were independently associated with postoperative recurrence. Three-, 5-, and 7-year overall survival rates after surgery were 100%, 80%, and 64% in obese patients and 100%, 92%, and 82% in non-obese patients, respectively (P = .014). However, other variables showed no significant difference in the overall survival rate. CONCLUSIONS: Obesity and non-anatomical resection were independent risk factors for HCC recurrence after hepatic resection and successful IFN therapy. Obesity is an important clinical problem to consider to improve postoperative outcomes in such patients.

AIM associated with the IgM pentamer: attackers on stand-by at aircraft carrier.

Circulating immunoglobulin M (IgM) exists in a pentameric form, possessing a polyreactive nature that responds not only to foreign antigens but also to autoantigens; thus, it is involved in both beneficial and detrimental immune responses, including protection from infection and the progression of autoimmunity. On the other hand, IgM also behaves as a carrier of the apoptosis inhibitor of macrophage (AIM) protein, storing a large amount of the inactivated form of AIM in the blood through this association. Under different disease conditions, AIM can dissociate from IgM locally or systemically to exert its function, inducing the removal of various biological debris such as excess fat, bacteria, cancer cells or dead cell debris. Most typically, upon induction of acute kidney injury (AKI), IgM-free AIM is filtered by the glomerulus in the kidney, which stimulates the clearance of intraluminal dead cells debris at the obstructed proximal tubules, thereby facilitating the repair of kidney injury. Interestingly, cats exhibit a deficiency in AIM release from IgM, which may increase their susceptibility to renal failure. Conversely, association with AIM inhibits IgM binding to the Fcα/µ receptor on follicular dendritic cells at the splenic germinal center, thereby protecting the IgM immune complex from Fcα/µ receptor-mediated internalization, which supports IgM-dependent antigen presentation to B cells and stimulates high-affinity IgG antibody production. The regulation of AIM-IgM binding, resulting from the discovery of reciprocal actions between AIM and IgM, could lead to the development of novel therapies against different diseases.