Endoscopic duodenal stent placement versus gastrojejunostomy for unresectable pancreatic cancer patients with duodenal stenosis before introduction of initial chemotherapy (GASPACHO study): a multicenter retrospective study.

BACKGROUND: Endoscopic duodenal stent placement is an alternative technique to gastrojejunostomy for gastric outlet obstruction due to pancreatic cancer. We compared the efficacy of endoscopic duodenal stent placement with that of gastrojejunostomy for treating patients with pancreatic cancer who are candidates for intensive combination chemotherapies as the first line of treatment. METHODS: This retrospective observational study included 100 patients from 18 institutions in Japan. Inclusion criteria were as follows: (1) cytologically or histologically confirmed adenocarcinoma of the pancreas, (2) good performance status, (3) gastric outlet obstruction scoring system score of 0-1 and (4) no history of treatment for pancreatic cancer. RESULTS: There was no significant difference in the background characteristics of patients in the endoscopic duodenal stent placement (n = 57) and gastrojejunostomy (n = 43) groups. The median overall survival in the endoscopic duodenal stent placement and gastrojejunostomy groups was 5.9 and 6.0 months, respectively. Clinical success was achieved in 93 cases; the median time to food intake resumption was significantly shorter in the endoscopic duodenal stent placement group (median: 3 days, n = 54) than in the gastrojejunostomy group (median: 5 days, n = 43). Chemotherapy was introduced in 63% of the patients in both groups after endoscopic duodenal stent placement or gastrojejunostomy. Chemotherapy was started earlier in the endoscopic duodenal stent placement group (median: 14 days) than in the gastrojejunostomy (median: 32 days) group. CONCLUSIONS: Endoscopic duodenal stent placement showed similar or better clinical outcomes than gastrojejunostomy. Thus, it might be a promising option in patients with good performance status.

Efficacy of chemotherapy in elderly patients with unresectable pancreatic cancer: a multicenter review of 895 patients.

BACKGROUND: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. METHODS: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. RESULTS: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%). CONCLUSIONS: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.

Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan.

BACKGROUND: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far. METHODS: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G>A) and p.Y67H (c.157C>T) for comparison. RESULTS: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells. CONCLUSION: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns.

[Regulation of leukemic stem cells by manipulating the Geminin activity].

Geminin regulates cellular proliferation and differentiation through the inhibition of DNA replication licensing and chromatin remodeling, respectively, to sustain the activity of hematopoietic stem cells (HSCs) and possibly that of leukemic stem cells (LSCs). Thus, Geminin is presumed to act as a cell fate determinant by turning on and off self-renewal and differentiation of the stem cells. We visualized Geminin expression by generating knock-in mice expressing Geminin fusion protein with enhanced yellow fluorescent protein. We further established a new method for manipulating the Geminin expression level and activity by generating cell -penetrating (CP) - Geminin. Here we argue for a new strategy for expanding HSCs ex vivo to provide a cellular source of HSCs for transplantation and further for eradicating LSCs, which are resistant to conventional chemotherapy.

Improvement of long-term outcomes in pancreatic cancer and its associated factors within the gemcitabine era: a collaborative retrospective multicenter clinical review of 1,082 patients.

BACKGROUND: Although the outcomes of pancreatic cancer have been improved by gemcitabine, the changes in its characteristics and long-term outcomes within the gemcitabine era remain unclear. This study was conducted to identify clinical characteristics of pancreatic cancer patients within the gemcitabine era. METHODS: A retrospective chart review was performed at 10 centers for 1,248 consecutive patients who were ever considered to have a diagnosis of pancreatic cancer between 2001 and 2010. Data collected included demographics, diagnosis date, clinical stage, treatment, and outcome 1,082 patients met the inclusion criteria and were analyzed further. The chi-square test, Student's t-test, and Mann-Whitney U-test were used for statistical analysis. Outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Differences in survival analyses were determined using the log-rank test. RESULTS: The distribution of clinical stages was: I, 2.2% II, 3.4% III, 13% IVa, 27% and IVb, 55%. Chemotherapy alone was administered to 42% of patients and 17% underwent resection. The 1-, 3-, and 5-year survival rates were 39%, 13%, and 6.9%, respectively. The median survival time was 257 days, but differed considerably among treatments and clinical stages. Demographics, distribution of clinical stage, and cause of death did not differ between groups A (2001-2005, n=406) and B (2006-2010, n=676). However, group B included more patients who underwent chemotherapy (P<0.0001) and fewer treated with best supportive care (P=0.0004), mirroring improvements in this group's long-term outcomes (P=0.0063). Finally, factors associated with long-term outcomes derived from multivariate analysis were clinical stage (P<0.0001), location of the tumor (P=0.0294) and treatments (surgery, chemotherapy) (<0.0001). CONCLUSIONS: Long-term outcomes in pancreatic cancer has improved even within the gemcitabine era, suggesting the importance of offering chemotherapy to patients previously only considered for best supportive care. Most patients are still diagnosed at an advanced stage, making clinical strategy development for diagnosing pancreatic cancer at earlier stages essential.

Hoxb4 transduction down-regulates Geminin protein, providing hematopoietic stem and progenitor cells with proliferation potential.

Retrovirus-mediated transduction of Hoxb4 enhances hematopoietic stem cell (HSC) activity and enforced expression of Hoxb4 induces in vitro development of HSCs from differentiating mouse embryonic stem cells, but the underlying molecular mechanism remains unclear. We previously showed that the HSC activity was abrogated by accumulated Geminin, an inhibitor for the DNA replication licensing factor Cdt1 in mice deficient in Rae28 (also known as Phc1), which encodes a member of Polycomb-group complex 1. In this study we found that Hoxb4 transduction reduced accumulated Geminin in Rae28-deficient mice, despite increasing the mRNA, and restored the impaired HSC activity. Supertransduction of Geminin suppressed the HSC activity induced by Hoxb4 transduction, whereas knockdown of Geminin promoted the clonogenic and replating activities, indicating the importance of Geminin regulation in the molecular mechanism underlying Hoxb4 transduction-mediated enhancement of the HSC activity. This facilitated our investigation of how transduced Hoxb4 reduced Geminin. We showed in vitro and in vivo that Hoxb4 and the Roc1 (also known as Rbx1)-Ddb1-Cul4a ubiquitin ligase core component formed a complex designated as RDCOXB4, which acted as an E3 ubiquitin ligase for Geminin and down-regulated Geminin through the ubiquitin-proteasome system. Down-regulated Geminin and the resultant E2F activation may provide cells with proliferation potential by increasing a DNA prereplicative complex loaded onto chromatin. Here we suggest that transduced Hoxb4 down-regulates Geminin protein probably by constituting the E3 ubiquitin ligase for Geminin to provide hematopoietic stem and progenitor cells with proliferation potential.

Patients with Chronic Liver Disease under Surveillance for Hepatocellular Carcinoma Have a Favorable Long-Term Outcome for Pancreatic Cancer Due to Early Diagnosis and High Resection Rate.

Patients with viral hepatitis-related chronic liver disease (CLD) under surveillance for hepatocellular carcinoma (HCC) are often diagnosed with pancreatic cancer (PC) at an early stage. However, the long-term outcomes of these patients are unclear. We aimed to clarify the long-term outcomes of patients with PC with viral hepatitis-related CLD using a chart review. Data collection included the Union for International Cancer Control (UICC) stage at PC diagnosis, hepatitis B virus and hepatitis C virus status, and long-term outcomes. The distribution of the entire cohort (N = 552) was as follows: early stage (UICC 0-IB; n = 52, 9.5%) and non-early stages (UICC IIA-IV; n = 500, 90.5%). At diagnosis, the HCC surveillance group (n = 18) had more patients in the early stages than the non-surveillance group (n = 534) (50% vs. 8.0%), leading to a higher indication rate for surgical resection (72.2% vs. 29.8%) and a longer median survival time (19.0 months vs. 9.9 months). We confirmed that patients with viral hepatitis-related CLD under HCC surveillance were diagnosed with PC at an early stage. Because of the higher indication rate for surgical resection in these patients, they had favorable long-term outcomes for PC.

Prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer.

Background: Zinc deficiency during long-term chemotherapy and its related symptoms, including skin rash, taste disorders, and oral mucositis, have not been sufficiently investigated. Methods: This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guidelines for Zinc Deficiency, zinc deficiency is defined as a serum level of <60 µg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results: Of the 61 enrolled patients, 48 who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin were analyzed. Zinc deficiency was observed in 18 patients (38%) before chemotherapy. The least-squares means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both P<0.01) but not in 18 with zinc deficiency at the beginning. Changes in serum zinc levels during chemotherapy negatively correlated with changes in taste, rash, and itching (all P<0.04) in patients without zinc deficiency before treatment initiation. Conclusions: Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the beginning of chemotherapy and correlated with taste changes, skin rash, and itching. Therefore, investigating whether zinc supplementation ameliorates these symptoms is necessary.

Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity.

Polycomb-group (PcG) genes encode multimeric nuclear protein complexes, PcG complex 1 and 2. PcG complex 2 was proved to induce transcription repression and to further methylate histone H3 at lysine-27 (H3K27). Subsequently PcG complex 1 is recruited through recognition of methylated H3K27 and maintains the transcription silencing by mediating monoubiquitination of histone H2A at lysine-119. Genetic evidence demonstrated a crucial role for PcG complex 1 in stem cells, and Bmi1, a member of PcG complex 1, was shown to sustain adult stem cells through direct repression of the INK4a locus encoding cyclin-dependent kinase inhibitor, p16CKI, and p19ARF. The molecular functions of PcG complex 1, however, remain insufficiently understood. In our study, deficiency of Rae28, a member of PcG complex 1, was found to impair ubiquitin-proteasome-mediated degradation of Geminin, an inhibitor of DNA replication licensing factor Cdt1, and to increase protein stability. The resultant accumulation of Geminin, based on evidence from retroviral transduction experiments, presumably eliminated hematopoietic stem cell activity in Rae28-deficient mice. Rae28 mediates recruiting Scmh1, which provides PcG complex 1 an interaction domain for Geminin. Moreover, PcG complex 1 acts as the E3 ubiquitin ligase for Geminin, as we demonstrated in vivo as well as in vitro by using purified recombinant PcG complex 1 reconstituted in insect cells. Our findings suggest that PcG complex 1 supports the activity of hematopoietic stem cells, in which high-level Geminin expression induces quiescence securing genome stability, by enhancing cycling capability and hematopoietic activity through direct regulation of Geminin.

Simple prognostic markers for optimal treatment of patients with unresectable pancreatic cancer.

ABSTRACT: Most patients with pancreatic cancer are ineligible for curative resection at diagnosis, resulting in poor prognosis. This study aimed to evaluate the prognostic factors in patients with unresectable pancreatic cancer.We retrospectively collected clinical data from 196 patients with unresectable pancreatic cancer who received palliative chemotherapy (N = 153) or palliative care alone (N = 43) from January 2011 to December 2013. Patients' background data and overall survival were analyzed using the Cox proportional hazard regression model.In patients receiving palliative chemotherapy (gemcitabine-based regimen, 88.2%) and palliative care alone, the median (range) ages were 68 (43-91) and 78 (53-90) years, and metastatic diseases were present in 80% (N = 123) and 86% (N = 37), respectively. Multivariate analysis in the palliative chemotherapy patients showed that liver metastasis (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.58-3.20, P < .001), neutrophil-to-lymphocyte ratio (>4.5 vs ≤4.5; HR 3.45, 95% CI 2.22-5.36, P < .001), and cancer antigen 19-9 (CA19-9) (≥900 vs <900 U/mL; HR 1.45, 95% CI 1.02-2.05, P = .036) were independent prognostic factors. In those receiving palliative care alone, lung (HR 3.27, 95% Cl 1.46-7.35, p = 0.004) and peritoneum (HR 2.50, 95% CI 1.20-5.18, P = .014) metastases and the C-reactive protein-to-albumin ratio (≥1.3 vs <1.3; HR 3.33, 95% Cl 1.51-7.35, P = .003) were independent prognostic factors. Furthermore, patients with multiple factors had worse prognosis in both groups. Median survival time of palliative chemotherapy patients with risk factors 0, 1, 2, and 3 were 13.1 (95% CI 8.0-16.9), 9.4 (95% CI 7.9-10.1), 6.6 (95% CI 4.9-7.8), and 2.5 (95% CI 1.7-4.0) months, respectively. Similarly, median survival time was 5.7 (95% CI 1.3 -8.0), 2.1 (95% CI 1.5-3.9), and 1.3 (95% CI 0.6-1.7) months, respectively, for palliative care alone patients with risk factor 0, 1, and 2 to 3.Prognostic markers for pancreatic cancer were neutrophil-to-lymphocyte ratio, liver metastasis, and CA19-9 in patients undergoing palliative chemotherapy and C-reactive protein-to-albumin ratio and lung/peritoneum metastases in patients undergoing palliative care alone. These simple markers should be considered when explaining the prognosis and therapeutic options to patients.

ABO Blood Type and the Long-term Outcomes of Pancreatic Cancer.

Objective The long-term effect of the ABO blood type on the clinical course of patients with pancreatic cancer (PC) is inconclusive. This study aimed to determine whether or not the ABO blood type influences the long-term outcomes of PC in Japanese patients. Methods The medical records of Japanese patients with PC were reviewed. Data, including the age, sex, and outcomes, from the Ehime Pancreato-Cholangiology Study Group were analyzed. Results The mean age of the 406 patients was 71.0±10.5 years, and 220 (54.2%) were men. A total of 44.6%, 20.7%, 22.4%, and 12.3% had blood type A, B, O, and AB, respectively. The median survival time (MST) of patients with A alleles was shorter than that of patients with non-A alleles (p=0.048), especially among those who underwent resection (p=0.031). In contrast, no marked difference in the MST was noted among those who underwent chemotherapy and palliative care. Finally, a multivariate analysis confirmed A alleles as an independent factor associated with the long-term outcome of PC (p<0.05 in 2 different models). Conclusion The ABO blood type influenced the long-term outcomes of Japanese patients with PC, presumably due to its impact on disease onset and tumor behavior.

Inference-assisted intelligent crystallography based on preliminary data.

Crystal structure analysis is routinely used to determine atomically resolved molecular structures and structure-property relationships. The accumulation of reliable structural characteristics obtained by crystal structure analysis has forged a robust basis that is frequently used in molecular and materials sciences. However, experimental techniques remain hampered by time-consuming 'blind' measurement-analysis iterations, which are sometimes required to find appropriate crystals and experimental conditions. Herein, we present a method that uses a small preliminary data set to evaluate the to-be-observed structures and the to-be-collected data. Moreover, we demonstrate the practical utility of this method to improve the efficiency of crystal structure analysis. This method will help selecting suitable crystals and choosing favorable experimental conditions to generate results that satisfy the level of precision required for specific research objectives.

Early Detection of Pancreatic Cancer in Patients With Chronic Liver Disease Under Hepatocellular Carcinoma Surveillance.

OBJECTIVE: To evaluate whether patients with hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic liver disease were diagnosed as having pancreatic cancer (PC) at an early stage during abdominal imaging surveillance for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively examined 447 patients with PC diagnosed at Ehime University Hospital and affiliated centers (2011-2013). Data were collected regarding HBV and HCV status, likelihood of PC diagnosis, and Union for International Cancer Control (UICC) stage. Intergroup comparisons were performed using the χ2 test. RESULTS: The UICC stage distribution in the HCC surveillance group (n=16) was stage 0 (n=2, 12.5%), stage IA (n=3, 18.8%), stage IB (n=2, 12.5%), stage IIA (n=2, 12.5%), stage IIB (n=2, 12.5%), stage III (n=1, 6.3%), and stage IV (n=4, 25%). The UICC stage distribution in the nonsurveillance group (n=431) was stage 0 (n=4, 0.9%), stage IA (n=28, 6.5%), stage IB (n=27, 6.3%), stage IIA (n=86, 20.0%), stage IIB (n=48, 11.1%), stage III (n=56, 13.0%), and stage IV (n=182, 42.2%). The HCC surveillance group had significantly more patients with stage 0 disease than with stages IA through IV (P=.02). Similar results were observed when including stages IA (P=.007) and IB (P=.004) as early stages but not stage IIA (P=.10). A dilated pancreatic duct led to a PC diagnosis in all 6 patients with stage 0 disease. CONCLUSION: Patients with HBV- and HCV-related chronic liver disease had an early PC diagnosis during HCC surveillance. Careful evaluation of the pancreas is warranted during HCC surveillance.

The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-gamma receptor 1 and has a dominant-negative effect on interferon-gamma signal transduction.

BACKGROUND: Patients with interferon-gamma receptor 1 (IFNgammaR1) deficiency show selective susceptibility to intracellular pathogens such as mycobacteria. IFNgammaR1 deficiency is an inherited immunodeficiency disorder, which can be either recessive or dominant. Dominant forms of IFNgammaR1 deficiency are known to be associated with mutations that introduce a premature stop codon in the intracellular domain of IFNgammaR1. One such mutation, 818del4, is believed to be the most common type. Although these mutations are presumed to exert a dominant-negative effect on IFNgamma signal transduction, the underlying molecular mechanism is unresolved. OBJECTIVE: We characterised the 774del4 mutant of IFNgammaR1 using a gene-expression system to examine the effects of this mutation on IFNgamma signal transduction. RESULTS: We identified a novel dominant mutation in IFNGR1, designated 774del4, which produced a truncated form of IFNgammaR1 in a patient with recurrent mycobacterial infections. IFNgammaR1 was overexpressed on the surfaces of CD14-positive cells from the peripheral blood of this patient, and STAT1 phosphorylation in response to high doses of IFNgamma was partially deficient. We expressed two truncated forms of IFNgammaR1, 774del4 and 818del4, in HEK 293 cells using transient transfection and found that these mutants overexpressed IFNgammaR1 on the cell surface because of impaired receptor stability, which resulted in a dominant-negative effect on IFNgamma signal transduction. CONCLUSION: Like the 818del4 mutation, 774del4 produces a truncated form of IFNgammaR1, which has a dominant-negative effect on IFNgamma signal transduction through altered receptor stability.

Usefulness of laparoscopy and intraductal ultrasonography in a patient with isolated immunoglobulin G4-related sclerosing cholangitis.

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is often associated with type 1 autoimmune pancreatitis, and the frequency of isolated IgG4-SC seems to be quite low, making the diagnosis of isolated IgG4-SC challenging. A 63-year-old male was admitted to our hospital for frequent fever. Abdominal magnetic resonance cholangiopancreatography showed diffuse narrowing of the common bile duct and post-stenotic dilatation of the right posterior bile duct. Laboratory tests showed abnormalities in the levels of hepatobiliary enzymes and serum IgG4 levels. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of intrahepatic bile ducts and post-stenotic dilatation of the right posterior bile duct but no abnormalities in the pancreas. Intraductal ultrasonography showed symmetric circumferentially thickened walls of both narrowed and non-narrowed common bile ducts. Histologic examination of the common bile duct mucosa showed infiltration of IgG4-positive plasma cells. Laparoscopic observations showed discoloration with red lobular markings and multiple small depressed lesions. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. From these findings, the patient was diagnosed with isolated IgG4-SC. After treatment with a steroid, bile duct dilatations improved. Laparoscopy and intraductal ultrasonography were useful to diagnose isolated IgG4-SC.

Diagnostic Challenge in Pancreatic Sarcoidosis Using Endoscopic Ultrasonography.

We herein report a 55-year-old woman who presented with erythema and bilateral hilar lymphadenopathy 4 months prior to the detection of pancreatic lesions on an ultrasound. A skin biopsy showed evidence of sarcoidosis. The largest lesion in the tail of the pancreas was hypoechoic on endoscopic ultrasonography (EUS). The lesion was initially iso-enhanced on contrast enhanced-EUS (CE-EUS) but subsequently became hypoenhanced. The lesion revealed heterogeneous components of both soft and hard tissue on EUS elastography. She was ultimately diagnosed with pancreatic sarcoidosis based on the presence of noncaseating granulomas seen on pancreatic tissue retrieved through an EUS-guided fine needle aspiration biopsy.

[Case of pancreatic endocrine tumor associated with Cushing's syndrome].

A 78-year-old woman was admitted complaining of edema of the bilateral lower extremities and face. Computed tomography (CT) and ultrasonography (US) of her abdomen revealed a pancreatic tumor and multiple liver metastases. After admission, hypokalemia and muscle weakness and edema of the bilateral lower extremities rapidly worsened. The diagnosis of Cushing's syndrome was established based on clinical and biochemical data and endocrine studies. We thought that the primary tumor was a pancreatic endocrine tumor based on the liver tumor biopsy findings, and that the pancreatic tumor and liver metastatic tumors were ectopic ACTH-producing tumors. A case of pancreatic endocrine tumor associated with Cushing's syndrome is relatively rare. We summarize previous reports.

Bayesian inference of metal oxide ultrathin film structure based on crystal truncation rod measurements.

Monte Carlo (MC)-based refinement software to analyze the atomic arrangements of perovskite oxide ultrathin films from the crystal truncation rod intensity is developed on the basis of Bayesian inference. The advantages of the MC approach are (i) it is applicable to multi-domain structures, (ii) it provides the posterior probability of structures through Bayes' theorem, which allows one to evaluate the uncertainty of estimated structural parameters, and (iii) one can involve any information provided by other experiments and theories. The simulated annealing procedure efficiently searches for the optimum model owing to its stochastic updates, regardless of the initial values, without being trapped by local optima. The performance of the software is examined with a five-unit-cell-thick LaAlO3 film fabricated on top of SrTiO3. The software successfully found the global optima from an initial model prepared by a small grid search calculation. The standard deviations of the atomic positions derived from a dataset taken at a second-generation synchrotron are ±0.02 Šfor metal sites and ±0.03 Šfor oxygen sites.

Downregulation of ANP32B exerts anti-apoptotic effects in hepatocellular carcinoma.

The acidic (leucine-rich) nuclear phosphoprotein 32 family member B (ANP32B), a highly conserved member of the acidic nuclear phosphoprotein 32 (ANP32) family, is critical for the development of normal tissue. However, its role in the development of hepatocellular carcinoma (HCC) is controversial. In this study, we elucidated the role of ANP32B in HCC cell lines and tissues. ANP32B expression in HCC cell lines was modulated using siRNA and ANP32B expression plasmids and lentiviruses. The levels of apoptosis-related proteins were analyzed by real-time RT-PCR and Western blotting. The expression of ANP32B in tissues from patients with HCC was investigated using real-time RT-PCR and immunohistochemistry. ANP32B knockdown by siRNA altered the expression of apoptosis-related proteins in HCC cell lines and reduced the expression of cleaved forms of caspase 3 and caspase 9, but not that of caspase 8, in HCC cells cultured with the pro-apoptotic agent staurosporine. Phosphorylated Bad was upregulated, whereas Bak was downregulated. Moreover, ABT-737, which binds to and inhibits anti-apoptotic proteins of the Bcl-2 family, rendered HCC cells resistant to apoptosis induced by ANP32B silencing. Conversely, ANP32B overexpression decreased Bad phosphorylation and upregulated Bak, but did not induce apoptosis because Bax expression was downregulated. In tissues from patients with HCC, a low tumor/non-tumor ratio of ANP32B mRNA expression was related to advanced UICC stage (p = 0.032). TUNEL-positive cells were observed in parallel with ANP32B expression in HCC tissues. ANP32B modulates Bad phosphorylation as well as Bak and Bax expression, resulting in regulation of apoptosis in HCC. These findings indicate the potential value of ANP32B as a therapeutic target for HCC.

Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs).

Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin-proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity. Thus, Geminin is presumed to play an important role in determining cell fate, i.e., turning on and off cellular quiescence and proliferation/differentiation, in HSCs. We recently generated recombinant cell-penetrating Geminin (CP-Geminin), enabling rapid incorporation and withdraw of Geminin protein in cells. CP-Geminin may be useful in regulating the cell cycle and chromatin configuration. In this article, we summarize current information on the molecular functions of Geminin and the regulatory system for Geminin protein expression, and argue for the molecular role of Geminin in cell fate determination of HSCs, and future perspective of a new technology for manipulating the activities of HSCs and cancer stem cells (CSCs).