[Questionnaire Survey on Oral Care and Oral Troubles for Patients with Gastric Cancer Received Chemotherapy].

BACKGROUND: The actual situation of oral care and oral troubles for patients with gastric cancer received chemotherapy is not clear. METHODS: Questionnaire survey in the form of oral questions was performed for patients with gastric cancer who received chemotherapy from December 2021 to February 2022. The relevance between the survey results and background factors was examined using the χ2 test. RESULTS: We performed the questionnaire survey for 36 patients. Of the 36 patients, 29 patients received dental check-up before starting chemotherapy. Fourteen of the 29 patients(48%)continued the dental check-up. Of 14 patients who continued the dental check-up, 9 patients were 65 years or older, while 14 of 15 patients who discontinued the dental check-up were 65 years or older. Continuity of dental check-up was low among the elderly patients. The rate of dysgeusia were 78 vs 30% in the patients who adopted and who did not adopt oral care other than toothbrushing(p=0.01). The frequency of oral troubles was dysgeusia(47%), stomatitis(42%), and dry mouth(36%). The severity of the oral troubles was, in order, dysgeusia, dry mouth, and pain. The most common side effect due to chemotherapy causing decreased food intake was dysgeusia. CONCLUSIONS: Dysgeusia was the most frequent and severe oral trouble.

[Regimen Selection by Narrative Approach in Patients with Advanced Gastric Cancer-Paclitaxel or Nab-Paclitaxel?]

BACKGROUND: According to the sixth Gastric Cancer Treatment Guideline, the regimen included nab-paclitaxel(nab-PTX) is a conditional recommendation as second-line treatment for advanced gastric cancer. However, the selection criteria of nab-PTX is not clear. METHOD: Questionnaire survey as narrative approach on the problems of paclitaxel premedication, the symptoms due to paclitaxel containing alcohol, and infusion time was conducted for patients who had been treated with paclitaxel. RESULTS: Thirty-six patients answered the questionnaire. Nonelderly patients(<65 years)or patients without comorbid medications complained of dissatisfaction with the inconvenience due to premedication significantly more than elderly patients(≥65 years)or patients with comorbid medications. Females or nonelderly patients were significantly more troubled by sleepiness due to premedication than males or elderly patients. Eight out of 11 patients who had visited hospital by driving a car for first-line treatment were troubled by prohibition of driving on the day of treatment. Thirty out of 36 patients answered that they would feel benefits from 30-minutes shortening of infusion time. CONCLUSION: Questionnaire survey suggests that we may select the patients for nab-PTX properly by clarifying the inconvenience of daily life associated with premedication, the way of transportation for visiting hospital, and the benefits by shortening of infusion time.

Cord blood granulocyte Colony-Stimulating factor level as an optimal predictor of umbilical cord arteritis associated with brain injury at term equivalent age in preterm neonates.

OBJECTIVE: The study aimed 1) to evaluate the association between the presence or absence of umbilical cord arteritis (UCA) and the cord blood cytokine levels, and 2) morbidity and mortality of preterm neonates; and 3) to identify predictive markers for UCA of preterm neonates. STUDY DESIGN: In this single-center retrospective observational cohort study, preterm neonates born at gestational age (GA) < 36 weeks were categorized pathologically according to the severity of intrauterine inflammation; those without UCA as Group 1, those with UCA as Group 2, and those without any intrauterine inflammation as Group 3 (control), and subgroup analyses classified by their GA were performed. We compared morbidity and mortality, and eight representative cytokine levels in cord blood samples between the groups. Subsequently, receiver operating characteristics (ROC) curves for UCA diagnosis for each cytokine were created, and values of areas under the curve (AUC) were calculated to determine the optimal predictive markers. RESULTS: In total, 105 patients (36, 58, and 11 in Groups 1, 2, and 3, respectively) were included. Multivariate logistic analysis revealed that patients with UCA had higher incidence of brain injury (Odds Ratio [OR] = 8.53, P = 0.0049, 95% Confidence Interval [CI]: 1.91 - 38.0), at term equivalent age in the subgroup analysis with GA < 32 weeks. Although the median value of cord blood granulocyte colony-stimulating factor (G-CSF) was significantly higher in Group 2 than in Group 1 or 3, only the G-CSF level was found to be high in the subgroup analysis with GA < 32 weeks. For UCA diagnosis, the AUC values of G-CSF were the highest among eight cytokines including interleukin 6 (IL-6). These findings were similar in the subgroup analysis with GA < 32 weeks. CONCLUSIONS: Preterm neonates, especially born at GA < 32 week, had higher morbidity from　brain injury in the group with UCA. The cord blood G-CSF level was highly accurate for predicting UCA and could thus be used as an optimal biomarker.

Solid state 1H, 7Li, and 13C NMR studies on new ionic plastic crystals of crown ether-Li-TFSA complexes.

This study provides the first evidence that a Li ion can form ionic plastic crystals using crown ether with a bis-(trifluoromethanesulphonyl) amide (TFSA) anion. 1H, 7Li, and 13C nuclear-magnetic-resonance (NMR) measurements of the 15-crown-5-Li-TFSA complex revealed that the constituents underwent isotropic reorientation in the plastic crystalline phase. The NMR data of the 12-crown-4-Li-TFSA salt showed that the complex is a rotator crystal (the complexes are denoted as [Li 15C5] and [Li 12C4] in this paper). The X-ray diffraction (XRD) reflection patterns of the [Li 15C5] crystal recorded in the highest-temperature solid phase (plastic phase) could be indexed to a cubic structure. Conversely, [Li 12C4] could be fitted to a trigonal structure. In this study, [M (3n)Cn] (M = Li, Na, K; n = 4-6) complexes were also prepared, and NMR, DSC, XRD, and electrical conductivity measurements were performed. Based on these results, we additionally revealed that the [Na 15C5] and [K (15C5)2] complexes are also new rotator crystals. Single-crystal XRD measurements also revealed that the [Na 15C5] compound has two stable sites in the crystal. Activation energies of molecular motions in the [M (3n)Cn] crystals were estimated using 1H NMR relaxation time (T1 and T2) measurements. The electrical conductivity measurements of [Li 12C4], [Li 15C5], and [Na 15C5] showed high ionic conductivities (∼10-2 S cm-1).

Time-correlation functions for odd Langevin systems.

We investigate the statistical properties of fluctuations in active systems that are governed by nonsymmetric responses. Both an underdamped Langevin system with an odd resistance tensor and an overdamped Langevin system with an odd elastic tensor are studied. For a system in thermal equilibrium, the time-correlation functions should satisfy time-reversal symmetry and the antisymmetric parts of the correlation functions should vanish. For the odd Langevin systems, however, we find that the antisymmetric parts of the time-correlation functions can exist and that they are proportional to either the odd resistance coefficient or the odd elastic constant. This means that the time-reversal invariance of the correlation functions is broken due to the presence of odd responses in active systems. Using the short-time asymptotic expressions of the time-correlation functions, one can estimate an odd elastic constant of an active material such as an enzyme or a motor protein.

Nrf3 Functions Reversely as a Tumorigenic to an Antitumorigenic Transcription Factor in Obese Mice.

Tumor tissue includes cancer cells and their associated stromal cells, such as adipocytes, myocytes, and immune cells. Obesity modulates tumor microenvironment through the secretion of several inflammatory mediators by inducing adipogenesis and myogenesis. Previously, we indicated that tumor growth is promoted by a transcription factor nuclear factor erythroid 2-related factor 3 (NRF3) in human cancer cells. However, the impact of obesity on NRF3-mediated tumorigenesis remains unknown. Here we show that obesity reprograms the tumorigenic to the antitumorigenic function of Nrf3 using a diet-induced obese mouse model. Nrf3 knockdown decreased tumor growth in mice fed a normal diet (ND), whereas it reversely increased tumor growth in mice fed a high-fat diet (HFD). Then, the tumor tissues derived from Nrf3 knockdown or control cancer cells in ND- or HFD-fed mice were subjected to a DNA microarray-based analysis. Similar to the tumor formation results, the expressions of genes related to adipogenesis, myogenesis, and interferon-alpha response were reversed by obesity, implying an increase or recruitment (or both combined) of adipocytes, myocytes, and immune cells. Among these gene sets, we focused on adipocytes. We showed that Nrf3 knockdown reduced cancer cell growth in the preadipocyte culture medium, while the growth inhibitory effect of Nrf3 knockdown on cancer cells was abolished in the adipocyte culture medium. These results suggest the possibility that cancer-associated adipocytes secrete the potential reprogramming factor from the tumorigenic to the antitumorigenic function of Nrf3 in cancer cells.

Safety and Oncological Benefit of Hepatopancreatoduodenectomy for Advanced Extrahepatic Cholangiocarcinoma with Horizontal Tumor Spread: Shinshu University Experience.

BACKGROUND: Although hepatopancreatoduodenectomy (HPD) is the only means of achieving R0 resection of widespread extrahepatic cholangiocarcinoma, its safety and oncological benefit remain controversial because of its inherent high risk of mortality and morbidity. OBJECTIVE: The aim of this study was to retrospectively analyze short- and long-term outcomes and evaluate the safety and oncological benefit of this advanced procedure. METHODS: The study cohort comprised 37 consecutive patients who had undergone major HPD. Portal vein embolization was performed before surgery in 20 (54%) patients with future remnant liver volume < 35%. RESULTS: The median operative time and blood loss were 866 min and 1000 mL, respectively. Concomitant vascular resection was performed in five patients (14%). The overall morbidity and mortality rates were 100% and 5.4% (n = 2), respectively. Nineteen patients (51%) had major (Clavien-Dindo grade III or higher) complications, the most common being intra-abdominal infection (49%) and post-hepatectomy liver failure (46%, grade B/C: 32%/5%), followed by postoperative pancreatic fistula (30%, grade B/C). R0 resection was achieved in 31 patients (84%). The 1-, 3-, and 5-year overall survival (OS) rates were 83%, 48%, and 37%, respectively. In patients with R0 resection, 5-year OS was comparable between patients who had undergone major HPD and major hepatectomy alone (41% vs. 40%, p = non-significant). CONCLUSIONS: HPD is a valid treatment option for extensive cholangiocarcinoma, offering long-term survival benefit at the cost of relatively high but acceptable morbidity and mortality rates. HPD is advocated in selected patients provided that it is considered possible to achieve R0 resection.

Impact of Remnant Carcinoma in Situ at the Ductal Stump on Long-Term Outcomes in Patients with Distal Cholangiocarcinoma.

BACKGROUND: The management of positive ductal margins with carcinoma in situ (R1-CIS) after resection is controversial. The aim of this study was to evaluate the impact of R1-CIS on survival in patients who underwent resection for distal cholangiocarcinoma. METHODS: We enrolled 121 consecutive patients with distal cholangiocarcinoma. Poor prognostic factors were investigated by multivariable analysis, and we performed a stratified analysis to evaluate the impact of R1-CIS on survival in patients with or without prognostic factors. RESULTS: Multivariable analysis identified node-positive status as the prognostic factor (P = 0.003). Stratified by lymph node status, overall survival (OS) in the R0 group was significantly better than that in the R1-CIS group in node-negative patients (57.1% vs 30.0%; P < 0.050). Although OS was comparable between the two groups in node-positive patients (5-year OS: 22.2% vs 20.0%, respectively; P = not significant). Furthermore, OS in patients in whom R0 was achieved by additional resection was significantly better than that in patients with R1-CIS (5-year OS: 66.7% vs 30.0%, respectively; P < 0.050). CONCLUSIONS: Remnant CIS is associated with a poor prognosis in patients with node-negative distal cholangiocarcinoma. Every effort should be made to achieve negative bile duct margins.

Pathophysiological Potentials of NRF3-Regulated Transcriptional Axes in Protein and Lipid Homeostasis.

NRF3 (NFE2L3) belongs to the CNC-basic leucine zipper transcription factor family. An NRF3 homolog, NRF1 (NFE2L1), induces the expression of proteasome-related genes in response to proteasome inhibition. Another homolog, NRF2 (NFE2L2), induces the expression of genes related to antioxidant responses and encodes metabolic enzymes in response to oxidative stress. Dysfunction of each homolog causes several diseases, such as neurodegenerative diseases and cancer development. However, NRF3 target genes and their biological roles remain unknown. This review summarizes our recent reports that showed NRF3-regulated transcriptional axes for protein and lipid homeostasis. NRF3 induces the gene expression of POMP for 20S proteasome assembly and CPEB3 for NRF1 translational repression, inhibiting tumor suppression responses, including cell-cycle arrest and apoptosis, with resistance to a proteasome inhibitor anticancer agent bortezomib. NRF3 also promotes mevalonate biosynthesis by inducing SREBP2 and HMGCR gene expression, and reduces the intracellular levels of neural fatty acids by inducing GGPS1 gene expression. In parallel, NRF3 induces macropinocytosis for cholesterol uptake by inducing RAB5 gene expression. Finally, this review mentions not only the pathophysiological aspects of these NRF3-regulated axes for cancer cell growth and anti-obesity potential but also their possible role in obesity-induced cancer development.

New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis through the 20S proteasome.

Accumulating evidence has revealed that human cancers develop by sequentially mutating pivotal genes, including driver genes, and acquiring cancer hallmarks. For instance, cancer cells are addicted to the transcription factor NRF2 (NFE2L2), which is a driver gene that utilizes the cellular cytoprotection system against oxidative stress and metabolic pathway reprogramming for sustaining high growth. Our group has recently discovered a new addiction to the NRF2-related factor NRF3 (NFE2L3) in cancer. For many years, the physiological function of NRF3 remained obscure, in part because Nrf3-deficient mice do not show apparent abnormalities. Nevertheless, human cancer genome databases suggest critical roles of NRF3 in cancer because of high NRF3 mRNA induction in several cancer types, such as colorectal cancer and pancreatic adenocarcinoma, with a poor prognosis. We found that NRF3 promotes tumor growth and malignancy by activating ubiquitin-independent 20S proteasome assembly through inducing the expression of the proteasome maturation protein (POMP) chaperone and thereby degrading the tumor suppressors p53 and Rb. The NRF3-POMP-20S proteasome axis has an entirely different effect on cancer than NRF2. In this review, we describe recent research advances regarding the new cancer effector NRF3, including unclarified ubiquitin-independent proteolysis by the NRF3-POMP-20S proteasome axis. The expected development of cancer therapeutic interventions for this axis is also discussed.

Preoperative C-reactive protein-to-albumin ratio predicts long-term outcomes in extrahepatic cholangiocarcinoma patients.

BACKGROUND: Systemic inflammation may have prognostic value in some malignancies and association with lymph node metastasis. This study aimed to evaluate the impact of systemic inflammatory biomarkers on long-term and oncological outcomes as well as to assess the association between biomarkers with lymph node metastasis in extrahepatic cholangiocarcinoma patients. METHODS: We enrolled 271 consecutive patients who underwent surgical resection for extrahepatic cholangiocarcinoma. Poor prognostic factors were compared to identify the biomarkers that were most associated with overall survival (OS) and disease-free survival (DFS) using receiver operating characteristic curves and multivariable analysis. Furthermore, we evaluated the relationship between biomarkers and lymph node metastasis. RESULTS: Four and two biomarkers were predictive for OS and DFS, respectively, among which, the C-reactive protein-to-albumin ratio (CAR) had the highest area under the curve values (OS: 0.631, DFS: 0.624). Multivariable analysis showed that a high CAR was an independent prognostic factor for both OS and DFS (P = .002 and P < .001, respectively). Although a high CAR was not significantly correlated with lymph node metastasis (P = .645), carbohydrate antigen 19-9 showed a significant correlation (P < .001). CONCLUSIONS: Preoperative CAR is the most accurate prognostic factor for OS and DFS in extrahepatic cholangiocarcinoma patients and is independent of lymph node metastasis.

Fascin1 suppresses RIG-I-like receptor signaling and interferon-ß production by associating with IκB kinase ϵ (IKKϵ) in colon cancer.

Fascin1 is an actin-bundling protein involved in cancer cell migration and has recently been shown also to have roles in virus-mediated immune cell responses. Because viral infection has been shown to activate immune cells and to induce interferon-ß expression in human cancer cells, we evaluated the effects of fascin1 on virus-dependent signaling via the membrane- and actin-associated protein RIG-I (retinoic acid-inducible gene I) in colon cancer cells. We knocked down fascin1 expression with shRNA retrovirally transduced into a DLD-1 colon cancer and L929 fibroblast-like cell lines and used luciferase reporter assays and co-immunoprecipitation to identify fascin1 targets. We found that intracellular poly(I·C) transfection to mimic viral infection enhances the RIG-I/MDA5 (melanoma differentiation-associated gene 5)-mediated dimerization of interferon regulatory factor 3 (IRF-3). The transfection also significantly increased the expression levels of IRF-7, interferon-ß, and interferon-inducible cytokine IP-10 in fascin1-deleted cells compared with controls while significantly suppressing cell growth, migration, and invasion. We also found that fascin1 constitutively interacts with IκB kinase ϵ (IKKϵ) in the RIG-I signaling pathway. In summary, we have identified fascin1 as a suppressor of the RIG-I signaling pathway associating with IκB kinase ϵ in DLD-1 colon cancer cells to suppress immune responses to viral infection.

Impact of age on groin hernia profiles observed during laparoscopic transabdominal preperitoneal hernia repair.

BACKGROUND: How increasing age affects the characteristics of groin hernia remains uncertain. This study evaluated the association between age and the type of groin hernia, especially with respect to its multiplicity, observed during laparoscopic transabdominal preperitoneal (TAPP) hernia repair. METHODS: We retrospectively evaluated 634 consecutive patients with primary groin hernia who underwent laparoscopic TAPP repair between October 2000 and June 2017. Patients were stratified into 4 age groups: < 60 years, 60-69 years, 70-79 years, and 80 years or older. RESULTS: The incidence of occult contralateral hernia and multiple ipsilateral hernias increased significantly with each increasing age group: 7.3%, 10.4%, 12.7%, and 20.8% for occult contralateral hernia (p = 0.005), and 5.6%, 9.2%, 16.8%, and 21.7% for multiple ipsilateral hernias (p < 0.001), respectively. Univariate analyses showed that an older age (age ≥ 70 years) was the only factor significantly associated with the presence of multiple groin hernias (odds ratio, 2.69; 95% confidence interval, 1.89-3.81; p < 0.001). In patients with multiple ipsilateral hernias, the prevalent form in men was a pantaloons hernia, with an incidence of about 70% across all age groups, whereas in women it was groin hernias, with one component being a femoral hernia, an obturator hernia, or both. CONCLUSIONS: The multiple occurrence of groin hernias, either unilaterally or bilaterally, was a clinical feature in the elderly.

ß-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells.

Remarkable upregulation of the NRF2 (NFE2L2)-related transcription factor NRF3 (NFE2L3) in several cancer tissues and its correlation with poor prognosis strongly suggest the physiological function of NRF3 in tumors. Indeed, we had recently uncovered the function of NRF3, which promotes cancer cell proliferation by p53 degradation via the 20S proteasome. Nevertheless, the molecular mechanism underlying the induction of NRF3 gene expression in cancer cells is highly elusive. We herein describe that NRF3 upregulation is induced by the ß-catenin/TCF4 complex in colon cancer cells. We first confirmed high NRF3 mRNA expression in human colon cancer specimens. The genome database indicated that the human NRF3 gene possesses a species-conserved WRE sequence (TCF/LEF consensus element), implying that the ß-catenin/TCF complex activates NRF3 expression in colon cancer. Consistently, we observed that the ß-catenin/TCF4 complex mediates NRF3 expression by binding directly to the WRE site. Furthermore, inducing NRF3 activates cell proliferation and the expression of the glucose transporter GLUT1. The existence of the ß-catenin/TCF4-NRF3 axis was also validated in the intestine and organoids of Apc-deficient mice. Finally, the positive correlation between NRF3 and ß-catenin target gene expression strongly supports our conclusion. Our findings clearly demonstrate that NRF3 induction in cancer cells is controlled by the Wnt/ß-catenin pathway.

NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner.

Ribosomal RNAs (rRNAs) act as scaffolds and ribozymes in ribosomes, and these functions are modulated by post-transcriptional modifications. However, the biological role of base methylation, a well-conserved modification of rRNA, is poorly understood. Here, we demonstrate that a nucleolar factor, nucleomethylin (NML; also known as RRP8), is required for the N(1)-methyladenosine (m(1)A) modification in 28S rRNAs of human and mouse cells. NML also contributes to 60S ribosomal subunit formation. Intriguingly, NML depletion increases 60S ribosomal protein L11 (RPL11) levels in the ribosome-free fraction and protein levels of p53 through an RPL11-MDM2 complex, which activates the p53 pathway. Consequently, the growth of NML-depleted cells is suppressed in a p53-dependent manner. These observations reveal a new biological function of rRNA base methylation, which links ribosomal subunit formation to p53-dependent inhibition of cell proliferation in mammalian cells.

Spontaneous reattachment of dislocated endothelial graft after non-Descemet stripping automated endothelial keratoplasty: a case report.

BACKGROUND: Graft detachment is a complication of non-Descemet stripping automated endothelial keratoplasty (nDSAEK). We report a case of spontaneous reattachment of an extensively dislocated graft after nDSAEK. CASE PRESENTATION: A 54-year-old male underwent penetrating keratoplasty (PKP) for keratoconus in his left eye in 2001. Following graft opacity due to rejection, a second PKP was implemented in May 2014. The graft was kept in good condition after the reoperation and yet, visual acuity (VA) declined due to cataract. PEA+IOL was then performed in May 2015. Because edema appeared in the graft 6 months after the PEA+IOL, nDSAEK was carried out in May 2016. Although the donor graft well attached immediately after the nDSAEK, the graft was almost completely dislocated 3 h later except a temporal part. Air was reinjected into the anterior chamber on the following day and the detachment was resolved. Despite of the treatment, about 1/5 of the graft remained detached and the detachment deteriorated to 3/4 of the graft 9 days later. Because the patient could not decide whether to undergo another operation immediately, we decided to follow him up first and found that the partially detached graft reattached spontaneously 1 month later during the follow-up. Although the cornea had a mild edema remaining in the superior temporal area, his BCVA improved to 1.0. Three months later, the graft remained in position and the cornea kept its transparency. CONCLUSIONS: Spontaneous reattachment was observed during the follow-up in a case that had shown a comparatively extensive graft dislocation after nDSAEK.

Thyroid function in asphyxiated newborns who received hypothermia therapy.

BACKGROUND: Thyroid function in asphyxiated newborns who received hypothermia therapy and its relation to neurological outcome are not well described. METHODS: We performed a prospective study to measure thyroid function in 12 asphyxiated newborns who received hypothermia therapy. We measured serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) on admission, at 24, 72, and 96 h after birth, and at discharge (range, 17-54 days). The 12 newborns were divided into two groups based on the presence of brain injury on head magnetic resonance imaging (six in the abnormal imaging group and six in the normal imaging group), and thyroid function was compared between the two groups. RESULTS: Serum TSH was within the normal range in the 12 newborns. Serum FT3 and FT4 remained low at 24, 72, and 96 h after birth, and returned to normal range at discharge in the 12 newborns. There was no significant difference in serum TSH between the two groups, but serum FT3 at 96 h after birth, and serum FT4 at 72 and 96 h after birth, were significantly lower in the abnormal imaging group than in the normal imaging group (P = 0.02; P = 0.03; and P = 0.01, respectively). CONCLUSIONS: Asphyxiated newborns have transient low thyroid hormone levels at 24-96 h after birth. Serum FT3 and FT4 between 72 and 96 h after birth may predict brain injury in asphyxiated newborns.

Possible roles of the transcription factor Nrf1 (NFE2L1) in neural homeostasis by regulating the gene expression of deubiquitinating enzymes.

The transcription factor Nrf1 (NFE2L1) maintains protein homeostasis (proteostasis) by regulating the gene expression of proteasome subunits in response to proteasome inhibition. The deletion of the Nrf1 gene in neural stem/progenitor cells causes severe neurodegeneration due to the accumulation of ubiquitinated proteins in Purkinje cells and motor neurons (Nrf1 NKO mice). However, the molecular mechanisms governing this neurodegenerative process remain unclear. We demonstrate herein that the loss of Nrf1 leads to the reduced gene expression of the deubiquitinating enzymes (DUBs) but not proteasome subunits in Nrf1 NKO mice between P7 and P18. First, we show that K48-linked polyubiquitinated proteins accumulate in Nrf1-deficient Purkinje cells and cerebral cortex neurons. Nevertheless, loss of Nrf1 does not alter the expression and proteolytic activity of proteasome. A significantly reduced expression of deubiquitinating enzymes was also demonstrated in Nrf1-deficient cerebellar tissue using microarray analysis. The genome database further reveals species-conserved ARE, a Nrf1 recognition element, in the regulatory region of certain DUB genes. Furthermore, we show that Nrf1 can activate Usp9x gene expression related to neurodegeneration. Altogether these findings suggest that neurodegeneration in Nrf1 NKO mice may stem from the dysfunction of the ubiquitin-mediated regulation of neuronal proteins.

Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection.

AIM: Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non-B non-C hepatocellular carcinoma (NBNC-HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC-HCC. METHODS: Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti-HBV core/surface antibodies in addition to HBV surface antigen and anti-hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake-positive group (ethanol intake >20 g/day, n = 31), non-alcoholic fatty liver group (steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (no ethanol intake or steatosis, n = 16). Preoperative clinical parameters, tumor and background liver pathology, and prognosis were analyzed. RESULTS: Advanced fibrosis and steatosis were detected in 64% and 60% of all patients, respectively. Approximately 85% of the alcohol intake-positive patients had advanced fibrosis. Non-alcoholic fatty liver HCC subjects had the highest body mass index and prevalence of diabetes, but 30-40% had none to mild fibrosis. The cryptogenic group of HCC patients had the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups. CONCLUSIONS: Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection.