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Abstract Worldwide, silicified woods are found in many geological formations. Significantly, the organic materials of wood are no longer dominant; almost all wood fossils have been mineralized into inorganic silica materials. These unique geological processes must be understood to develop better understanding on organic material fossilization, particularly in the micron scale. Therefore, our aim was to characterize the composition of silicified wood using comprehensive microanalysis. The methods utilized were XRF, ICP-MS, XRD, FTIR, and FE-EPMA. Specimens are from Jasinga, West Java, Indonesia. The results showed that wood silicification was controlled by the infiltration of silica from the host rock into the spaces of the wood structure. In Jasinga, they are controlled by Pliocene tuffaceous sedimentary rocks. The ratio of silica phases revealed a trend in the degree of silicification. Besides silica, the distribution of trace elements also demonstrates the geochemical interaction between the wood fossil and host rock. Wood fossils are affected by the gradual replacement of organic carbon-based materials with silica through silicification. Silica enrichment occurs in the internal of wood, facilitates permineralization and recrystallization. Silica replaces organic material and preserves the wood structures. The microanalytical approach provides comprehensive perspectives on wood petrification, leads to better insights for paleontological studies.

Abstract Background Waldenström’s macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL. Case presentation An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein. Conclusion Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.

Abstract Onoceroids are a rare family of triterpenes. One representative onoceroid is ambrein, which is the main component of ambergris used as a traditional medicine. We have previously identified the onoceroid synthase, BmeTC, in Bacillus megaterium and succeeded in creating ambrein synthase by introducing mutations into BmeTC. Owing to the structural similarity of ambrein to vitamin D, a molecule with diverse biological activities, we hypothesized that some of the activities of ambergris may be induced by the binding of ambrein to the vitamin D receptor (VDR). We demonstrated the VDR binding ability of ambrein. By comparing the structure–activity relationships of triterpenes with both the VDR affinity and osteoclastic differentiation-promoting activity, we observed that the activity of ambrein was not induced via the VDR. Therefore, some of the activities of ambergris, but not all, can be attributed to its VDR interaction. Additionally, six unnatural onoceroids were synthesized using the BmeTC reactions, and these compounds exhibited higher VDR affinity than that of ambrein. Enzymatic syntheses of onoceroid libraries will be valuable in creating a variety of bioactive compounds beyond ambergris.

Hypertrophic pachymeningitis (HP) is a rare inflammatory disease characterized by thickening of the dura mater. HP develops with several inflammatory diseases. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgG4 related disease are reported as 2 major causes. With hematologic diseases, only 3 cases have been reported. We report the case of myelodysplastic syndrome (MDS) developing HP. Our case provides a thought-provoking hypothesis regarding the potential relationship between MDS and HP.

Abstract Background Acinar cell carcinoma of the pancreas is a rare exocrine malignancy representing less than 1% of all pancreatic neoplasms. It has been reported that it responds to treatment differently from pancreatic ductal adenocarcinoma and the treatment algorithm for acinar cell carcinoma usually depends on the stage of the respective tumor and the patient’s current status. Case presentation A 60-year-old man presented with upper abdominal pain and anorexia. Abdominal ultrasonography showed a large-sized hepatic mass and he was referred to our hospital. Contrast-enhanced computed tomography demonstrated a 110-mm low-density area occupying the right hemi-liver and an enhanced mass of 70 × 56 mm in the tail of the pancreas, which seemed to directly infiltrate into the spleen. The case was diagnosed as acinar cell carcinoma with a simultaneous liver metastasis identified by liver biopsy. Upfront resection of pancreatic cancer with distant metastasis might not be considered as an optimal choice, and in this case chemotherapy was administered prior to curative resection. Chemotherapy using the modified FOLFIRINOX regimen was undertaken, resulting in a partial remission; the liver tumor reduced in size from 110 to 47 mm and the pancreatic tumor from 70 to 40 mm. The patient then safely underwent curative hepatic resection with distal pancreato-splenectomy. Histological examinations revealed small-sized atypical cells with large nuclei that had formed acinar patterns, and immunostaining with trypsin was positive in tumor cells, which was in accordance with acinar cell carcinoma. More than 3 years later, the patient is doing well without any recurrence. Conclusion Aggressive and curative surgery in combination with chemotherapy such as FOLFIRINOX could be a treatment option to achieve long-term survival in cases of acinar cell carcinoma with liver metastases.

Abstract Silicate glasses are durable materials in our daily life, but corrosion rate accelerates under alkaline aqueous environment. Such situation has raised concerns, for example, in nuclear waste disposal where vitrified wastes encounter to alkaline leachate from surrounding concrete materials. Here we report volcanic glass example surviving with a hyperalkaline groundwater (pH > 11) and high flow rate for about 4000 years. The tiny glass fragments were extracted from the volcanic ash layer sandwiched between ultramafic sediments using microanalytical techniques. Sharp elemental distributions at the glass surface, where amorphous-like smectite precursors and crystalline smectites coexist, suggest the corrosion by an interface-coupled dissolution–precipitation mechanism rather than inter-diffusion. The corrosion rate was maintained at, the minimum, 2.5 orders of magnitude less than the rate observed for fresh glass, even in the presence of Fe and Mg that might have consumed Si through the silicate precipitation.

It is important to understand the long-term migration of radionuclides when considering rock engineering projects such as the geological disposal of radioactive waste. The network of fractures and pores in a rock mass plays a major role in fluid migration as it provides a pathway for fluid flow. The geometry of a network can change due to fracture sealing by some fine-grained materials over long-term periods. Groundwater usually contains finegrained minerals such as clay minerals, and it is probable that the accumulation of such minerals occurs within a rock fracture upon groundwater flow, thereby decreasing the aperture of a fracture and the permeability. It is therefore essential to conduct permeability measurements using water that includes fine-grained minerals to understand the permeability characteristics of a rock; however, this has not been studied to date. In the present study, we use a macro-fractured granite sample to investigate the change of permeability that occurs under the flow of water that includes two different amounts of clay. Findings showed that clay accumulated in a fracture and that the permeability (hydraulic conductivity) of the granite sample decreased over time, which was greater in for the higher clay content. We concluded that the accumulation of clay minerals in the fracture decreased the permeability of the rock. Furthermore, we consider that the filling and closure of fractures in rock is possible under the flow of groundwater that includes clay minerals.

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

Abstract A 36‐year‐old man with severe acute kidney injury (AKI) was admitted to Shonan Kamakura General Hospital in Japan. He was diagnosed with refractory hypertension based on a severely elevated blood pressure of 224/116 mmHg and retinal, cardiac, and brain damage revealed by electrocardiogram, fundoscopy, and magnetic resonance imaging, respectively. Although hemodialysis was withdrawn following strict blood pressure control by an angiotensin receptor blocker, severe kidney insufficiency persisted. Therefore, we performed an autologous granulocyte colony‐stimulating factor‐mobilized peripheral blood CD34‐positive cell transplantation. Collected CD34‐positive cells were directly infused to both renal arteries. The patient's general condition was unremarkable after intervention, and the serum creatinine level gradually improved to 2.96 mg/dL 23 weeks after cell therapy. Although transient fever and thrombocytosis were observed after intervention, no major adverse events were observed. This patient is the first case in a phase I/II clinical trial of autologous granulocyte colony‐stimulating factor‐mobilized peripheral blood CD34‐positive cell transplantation for severe AKI with a CD34‐positive cell dose‐escalating protocol (trial number jRCTb030190231).

Soil organic matters may inhibit the pozzolanic reaction, and thus influence the strength development of soil-employed construction materials. To understand their interaction, the effect of lignosulfonate, here used as model soil organic matter, on the pozzolanic reaction was investigated through batch experiments. Lignosulfonate inhibited the pozzolanic reaction, suppressing calcium silicate hydrate (C-S-H) formation. The suppression did not take place in a continuous way with the addition of lignosulfonate but was triggered at a certain dosage of lignosulfonate. We propose that the inhibition was primarily due to formation of Si-(Ca)-lignosulfonate complex. Such interaction may illustrate the inhibition of the pozzolanic reaction by organic matters in soils at alkaline activation. Below the threshold, lignosulfonate allowed C-S-H formation though modified its structure, which also suggested the possibility of soil organic matters to influence the strength development of construction materials in coexistence of C-S-H formation.

Abstract Background Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma. Case presentation A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission. Conclusions This patient’s case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma.

In this study, we developed the electrical impedance method which simultaneously measures the thickness and breakdown ratio of oil films in elastohydrodynamic (EHD) line contacts within thrust needle roller bearings. Initially, we theoretically demonstrated that the oil film thickness and breakdown ratio can be simultaneously measured using the complex impedance that is produced when an AC voltage is applied to EHD line contacts. To verify the measurement accuracy of the electrical method, we monitored the oil film thickness of a thrust needle roller bearing and compared it with the theoretical value. The results revealed that the oil film thickness was thinner than the theoretical value immediately after starting the test, with the breakdown ratio being greater than 0 (indicating mixed lubrication); however, the breakdown ratio decreased over time, and the oil film thickness nearly matched the theoretical value one hour after starting the test, when it is believed that running-in wear is complete (i.e., breakdown ratio ≈ 0). Furthermore, following the test, after examining the race surface, we confirmed that running-in wear had indeed occurred. These results suggest that the developed method can monitor the lubrication conditions in EHD line contacts, such as those in thrust needle roller bearings, in detail.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Abstract Hot spring discharge was linked to the 2011 Mw 6.6 Iwaki earthquake. Periodic surveys revealed that the discharge continued for more than 7 years, which is a rare and valuable long-term record of hot spring discharge triggered by an earthquake in a non-volcanic area. In terms of coseismic changes, based on a comparison of the spatial distribution of changes in the coseismic water head and calculated crustal volumetric strain using a fault model, hot spring water discharge was found to be caused by a change in the coseismic crustal volumetric strain. As for the postseismic changes, observations over 7 years revealed a gradual rise in the temperature and chloride ion concentration of the hot spring water. Such long-term hot spring discharge may be explained by the following two causes: the rise of thermal water from the deep part and the permeability changes along the hot spring channels.

Abstract Evaluation of early response by flow cytometry and immunogloblin heavy chain assessments against primary bone marrow B‐cell lymphoma could be valuable for predicting treatment outcome.

Abstract The 2016 Kumamoto earthquake, whose main shock was an M7.3 event on April 16, 2016, 28 h after a foreshock of M6.5, caused severe damage in and around Kumamoto Prefecture, Japan. It also caused postseismic hydrological changes in Kumamoto Prefecture. In this study, we analyzed daily streamflow data collected by eight observation stations from 2001 to 2017 in regions that experienced strong ground motion during the 2016 Kumamoto earthquake. We also surveyed 11 water springs in the region several times after the main shock. Streamflow had no or slight change immediately after the earthquake; however, large increases were recorded at some of the eight stations following a heavy rainfall that occurred 2 months after the earthquake. A decrease in the water-holding capacity of the catchment caused by earthquake-induced landslides can explain this delayed streamflow increase. Conversely, earthquake-related changes to the spring flow rate were not so clear. Water temperature and chemical composition of spring waters were also hardly changed. Only the concentration of NO3 −, which is usually considered to be supplied from the surface, changed slightly just after the earthquake. These results show that the postseismic hydrological changes were caused mainly by earthquake-induced surface phenomena and that there was little contribution from hydrothermal fluid.

Although a significant association between periodontal disease and atherosclerotic cardiovascular disease has been reported, their cause-to-effect relationship remains controversial. This randomized controlled clinical trial aimed to investigate the effect of advanced self-care on atherosclerotic cardiovascular disease-related vascular function markers flow-mediated brachial artery dilatation (FMD) and serum asymmetric dimethylarginine (ADMA) level in patients with early-stage periodontal disease. The study was designed as a parallel group, 3-month follow-up, open-label, randomized controlled trial. The control group received standard care for periodontal diseases, whereas the test group additionally applied disinfectant using a custom-fabricated prescription tray for advanced self-care twice a day. Overall, 110 patients provided data for FMD and serum ADMA level. No significant improvements in FMD were observed in the control (mean increase, -0.1%; 95% confidence interval [CI], -1.0-0.8; P = 0.805) or test (mean increase, -0.3%; 95% CI, -1.1-0.4; P = 0.398) group. No significant changes in serum ADMA levels were observed (mean reduction, 0.01 μmol/L; 95% CI, -0.00-0.02; P = 0.366 and mean reduction, 0.00 μmol/L; 95% CI, -0.01-0.01; P = 0.349, respectively). No significant between-group differences were found in FMD (mean difference, -0.2%; 95% CI, -1.4-0.9; p = 0.708) or serum ADMA levels (mean difference, 0.01 nmol/L; 95% CI, -0.00-0.03; p = 0.122). Significant improvements in the average probing pocket depth were observed in the control and test groups. The bleeding on probing score in the test group was significantly reduced, while that in the control group was reduced, although not significantly. Periodontal care for a 3-month duration did not provide better endothelial function although improvements of periodontal status in patients with early-stage periodontal diseases. This trial is registered in UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/; ID: UMIN000023395).

Summary: Site-specific recombination (SSR) systems are employed for transfer of mobile genetic elements (MGEs), such as lysogenic phages and integrative conjugative elements (ICEs). SSR between attP/I and attB sites is mediated by an integrase (Int) and a recombination directionality factor (RDF). The genome of Bacillus subtilis 168 contains SPβ, an active prophage, skin, a defective prophage, and ICEBs1, an integrative conjugative element. Each of these MGEs harbors the classic SSR unit attL-int-rdf-attR. Here, we demonstrate that these SSR units are all compatible and can substitute for one another. Specifically, when SPβ is turned into a defective prophage by deletion of its SSR unit, introduction of the SSR unit of skin or ICE converts it back to an active prophage. We also identified closely related prophages with distinct SSR units that control developmentally regulated gene rearrangements of kamA (L-lysine 2,3-aminomutase). These results suggest that SSR units are interchangeable components of MGEs. : Genetics; Molecular Genetics; Microbiology; Microbial Genetics Subject Areas: Genetics, Molecular Genetics, Microbiology, Microbial Genetics

Summary: Background: Body weight loss (BWL) is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. The risk factors for severe BWL after gastrectomy remain unclear. Methods: The present study retrospectively examined patients who underwent curative gastrectomy for gastric cancer between January 2012 and June 2014 at Kanagawa Cancer Center. All patients received perioperative care based on the enhanced recovery after surgery protocol. The %BWL value was calculated based on the percentage of body weight at 1 month after surgery in comparison to the preoperative body weight. Severe BWL was defined as %BWL > 10%. The risk factors for severe BWL were determined by both univariate and multivariate logistic regression analyses. Results: There were 278 patients examined. The median age of the patients was 68 years. The operative procedures included total gastrectomy [n=97; open (n=61) and laparoscopic {n=36)] and distal gastrectomy (n=181). Surgical complications of grade ≥ 2 (as defined by the Clavien–Dindo classification) were observed in 37 patients, these included: pancreatic fistula (n=9), anastomotic leakage (n=5), and abdominal abscess (n=3). There were no cases of surgery-associated mortality. Both univariate and multivariate logistic analyses demonstrated that surgical complications, and total gastrectomy were significant risk factors for severe BWL. Conclusions: Surgical complications and total gastrectomy were identified as being significant risk factors for severe BWL in the 1st month after gastrectomy. To maintain body weight after gastrectomy, physicians should pay careful attention to patients who undergo total gastrectomy and those who develop surgical complications. : Synopsis: This report demonstrates for the first time that the type of gastrectomy and surgical complications were significant independent risk factors for severe body weight loss in patients who received perioperative care using an enhanced recovery after surgery program after gastrectomy. Keywords: body weight loss, gastrectomy, gastric cancer

Zambia’s Kabwe mine wastes (KMWs) are responsible for contaminating the surrounding soil and dust in the Kabwe district. Unfortunately, these wastes arise from the historical mining activities of lead (Pb) and Zinc (Zn), which lacked adequate waste management strategies. As a result, potentially toxic elements (PTEs) (Pb and Zn) spread across the Kabwe district. To assess the soil pollution derived from previous mining activities, we studied topsoil samples (n = 8) from the school playground soils (SPs). In this study, the degree of contamination, geochemical partitioning, and leachability, coupled with the release and retention of Pb and Zn, were studied. The SPs were classified as extremely enriched (EF > 40) and contaminated with Pb (Igeo > 5). On average, Pb (up to 89%) and Zn (up to 69%) were bound with exchangeable, weak acid-soluble, reducible and oxidizable phases, which are considered as ’geochemically mobile’ phases in the environment. The leachates from the soils (n = 5) exceeded the Zambian standard (ZS: 190:2010) for Pb in potable drinking water (Pb < 0.01 mg/L). Furthermore, the spatial distribution of Pb and Zn showed a significant reduction in contents of Pb and Zn with the distance from the mine area.

Abstract Background Serum C-reactive protein (CRP) level can be an indicator of the early stage of infectious complications. However, its utility in advanced esophageal cancer patients who receive radical esophagectomy with two- or three-field lymph node dissection with perioperative steroid therapy and enhanced recovery after surgery (ERAS) care is unclear. Methods The present study retrospectively examined 117 consecutive esophageal cancer patients who received neoadjuvant chemotherapy followed by radical esophagectomy. All patients received perioperative steroid therapy and ERAS care. The utility of the CRP value in the early detection of serious infectious complications (SICs) was evaluated based on the area under the receiver operating characteristic curve (AUC). Univariate and multivariate logistic regression analyses were performed to identify the risk factors for SICs. Results SICs were observed in 20 patients (17.1%). The CRP level on postoperative day (POD) 4 had superior diagnostic accuracy for SICs (AUC 0.778). The cut-off value for CRP was determined to be 4.0 mg/dl. A multivariate analysis identified CRP ≥ 4.0 mg/dl on POD 4 (odds ratio, 18.600; 95% confidence interval [CI], 4.610–75.200) and three-field lymph node dissection (odds ratio, 7.950; 95% CI, 1.900–33.400) as independent predictive factors. Conclusions CRP value on POD 4 may be useful for predicting SICs in esophageal cancer patients who receive radical esophagectomy with perioperative steroid therapy and ERAS care. This result may encourage the performance of imaging studies to detect the focus and thereby lead to the early medical and/or surgical intervention to improve short-term outcomes.

Background: Routine therapy of metabolic bone disorder (MBD) after gastrectomy for gastric cancer has not been established yet. We have reported that administering an active vitamin D3 agent to patients who had undergone gastrectomy for gastric cancer improved MBD. Recently, the usefulness of alendronate, an osteoclast inhibitor, has been reported for MBD. Here we report the effects of alendronate for MBD after gastrectomy for gastric cancer. Methods: Dual energy X-ray absorptiometry was performed consequently in 14 patients, who had been gastrectomized for gastric cancer and survived more than 5 years without recurrence, to evaluate the MBD and compared before and after treatment. The 14 patients were divided into two groups: in group VD3, 1 μg/d of alfacalcidol, an active vitamin D3 agent, was administered; and in group ALN, 5 mg/d or 35 mg/wk of alendronate or both alfacalcidol and alendronate were administered. These drugs had been administered to the patients for > 2 years, and the patients were followed up. Results: After 12 months, dual energy X-ray absorptiometry revealed that bone mineral density and T score were significantly increased in group ALN. Changes in serum bone-specific alkaline phosphatase after 24 months were −9.1 μg/L in the ALN group and 3.75 μg/L in the VD3 group, showing a significant difference (p = 0.02). No serious adverse events were observed in either group. Conclusion: These results showed the usefulness of alendronate and alendronate+activated vitamin D3 combination therapy, suggesting that these treatments might prevent postgastrectomic MBD.

Glucose is the most favorable carbon source for many bacteria, which have several glucose-responsive gene networks. Recently, we found that in Bacillus subtilis glucose induces the expression of the extracellular sigma factor genes sigX and sigM through the acetylation of CshA (RNA helicase), which associates with RNA polymerase (RNAP). We performed a transposon mutagenesis screen for mutants with no glucose induction (GI) of sigX-lacZ. While screening for such mutants, we recently found that the GI of sigX/M involves YlxR, a nucleoid-associated protein (NAP) that regulates nearly 400 genes, including metabolic genes. It has been shown that acetylated CshA positively regulates expression of ylxR-containing operon. Here, we report additional mutations in yqfO or tsaD required for the GI of sigX. YqfO contains a universally conserved domain with unknown function. YqfO and YlxR were found to regulate expression of the tsaEBD-containing operon. Mutational analysis using lacZ fusions revealed the adenine-rich cis-element for YlxR. TsaD is a component of the TsaEBD enzyme required for the synthesis of threonylcarbamoyl adenosine (t6A). The t6A modification of tRNA is universal across the three domains of life. Western blot analysis showed that the tsaD mutation in the presence of glucose reduced levels of soluble PdhA, PdhB, and PdhD, which are subunits of the pyruvate dehydrogenase complex (PDHc). This resulted in severely defective PDHc function and thus reduced concentrations of cellular acetyl-CoA, a reaction product of PDHc and plausible source for CshA acetylation. Thus, we discuss a suggested glucose-responsive system (GRS) involving self-reinforcing CshA acetylation. This self-reinforcing pathway may contribute to the maintenance of the acetyl-CoA pool for protein acetylation.

Spray dry granulation of clay minerals was studied to obtain clay mineral base support material for metallocene supported olefin polymerization catalysts. The morphology of the granules was strongly influenced by the nature of the clay mineral itself. Because of swelling characteristics of montmorillonite, its water dispersion was highly viscous even in the low slurry concentration (< 4 wt %). Therefore, it was very difficult to control the granule characteristics such as size, shape, and inside structure by the spray dry with the clay mineral slurry. Then we examined some methods in order to change the clay mineral surface properties for getting less viscous dispersion. It was found that the milling of montmorillonite increased the amount of surface OH groups. This surface characteristic change should promote the interaction between the edges and basal planes of the primary particles of milled montmorillonite, resulting in the lowering the slurry viscosity. The milling is effective for overcoming difficulty in use of high concentration montmorillonite slurry in spray dry granulation which is indispensable for producing granules in the wide range of size (10–50 μm). The spray-dried montmorillonite granules are useful as a "Support-Activator" for an olefin polymerization catalyst combined with metallocenes.

Zinc plant leach residues (ZPLRs) contain significant amounts of metal compounds of lead (Pb), zinc (Zn), iron (Fe), etc., hence, they are considered as a secondary source of metals. On the other hand, ZPLRs are regarded as hazardous materials because they contain heavy metals that pollute the environment. Resources and environmental concerns of ZPLRs were addressed in this study by removing/recovering Pb and Zn using a concurrent dissolution and cementation technique. To cement the dissolved Pb and Zn in leaching pulp, zero-valent aluminum (ZVAl) was added during ZPLRs leaching in the hydrochloric (HCl)–sodium chloride (NaCl) solution. The resulting cemented metals were agglomerated and separated by sieving. Lead removal increased with increasing both NaCl and HCl concentrations. However, when ZVAl was added, significant Pb removal was achieved at a low concentration. Zinc was not cemented out of the pulp using ZVAl and its recovery from ZPLRs was dependent on the HCl concentration only. By applying a concurrent dissolution and cementation technique, both Pb and Zn were removed using a low concentration of NaCl, and most importantly Pb—the most toxic metal in ZPLRs—was captured and separated before the solid-liquid separation, hence, eliminating the need for extensive washing of the generated residues to remove the inherent residual solution.

Abstract Organisms from all domains of life use gene regulation networks to control cell growth, identity, function, and responses to environmental challenges. Although accurate global regulatory models would provide critical evolutionary and functional insights, they remain incomplete, even for the best studied organisms. Efforts to build comprehensive networks are confounded by challenges including network scale, degree of connectivity, complexity of organism–environment interactions, and difficulty of estimating the activity of regulatory factors. Taking advantage of the large number of known regulatory interactions in Bacillus subtilis and two transcriptomics datasets (including one with 38 separate experiments collected specifically for this study), we use a new combination of network component analysis and model selection to simultaneously estimate transcription factor activities and learn a substantially expanded transcriptional regulatory network for this bacterium. In total, we predict 2,258 novel regulatory interactions and recall 74% of the previously known interactions. We obtained experimental support for 391 (out of 635 evaluated) novel regulatory edges (62% accuracy), thus significantly increasing our understanding of various cell processes, such as spore formation.

The genetic etiology of female infertility is almost completely unknown. Recently, the egg membrane protein JUNO was identified as a receptor of the sperm-specific protein IZUMO1 and their interaction functions in sperm-egg fusion in fertilization. In the present study, we examined 103 women with infertility of unknown etiology. We analyzed the JUNO gene in these cases by PCR and Sanger sequencing. We identified seven variants in total: four common, two synonymous, and a previously unidentified intronic mutation. However, it is not clear from these variants that JUNO has a major role, if any, in infertility. Many factors affect sterility and a larger cohort of patients will need to be screened in the future because the cause of female infertility is highly heterogeneous.

The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3-4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days); the same was true for days of mucositis grade 3-4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.

Radiation therapy (RTx) has been employed as a curative therapy for prostatic adenocarcinoma. RTx-induced sarcomas (RISs) are rare, late adverse events, representing less than 0.2% of all irradiated patients. RISs are more aggressive tumors than prostatic adenocarcinomas. Herein, we present a case with RTx-induced prostatic leiomyosarcoma after permanent brachytherapy for prostatic adenocarcinoma. A 69-year-old male presented with dysuria and gross hematuria. Six years previously, he had been diagnosed with localized prostate cancer and was treated by permanent brachytherapy. Urethroscopy showed stenosis by a tumor at the prostate. Transurethral prostatectomy was performed for a diagnosis. Based on pathological findings, the diagnosis was leiomyosarcoma of the prostate. He was treated with three cycles of neoadjuvant chemotherapy (CTx) that consisted of doxorubicin and ifosfamide (AI), followed by a prostatocystectomy with intrapelvic lymphadenectomy. The tumor extended from the prostate and infiltrated the bladder wall and serosa with lymphatic and venous invasion. The surgical margin was negative, and no residual prostatic adenocarcinoma was observed. The proportion of necrotic tumor cells by neoadjuvant CTx was around 50%. Subsequently, adjuvant CTx was offered, but the patient chose a follow-up without CTx. Local recurrence and lung metastasis were detected by computed tomography 3 months after the surgery. He was treated again with AI. However, CTx was not effective and he died 6 months after the operation. In conclusion, an effective treatment strategy for prostatic sarcoma should be developed in the near future, although the clinical feature of prostatic sarcoma remains unclear due to its rare incidence.

Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.

The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34+ cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34+ cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.

Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGFβ) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

Diamond-like carbon (DLC) is being advanced as an excellent surface modification technology for a growing number of applications because of its low friction coefficient and excellent wear resistance. Due to the excellent characteristics of certain mechanical elements, such as a bearing, high levels of functionality are expected. Unfortunately, it is difficult to take full advantage of such high functionality because of insufficient endurance under high-pressure operating conditions. In order to make use of DLC as a bearing surface coating, the mechanism of DLC delamination under high-pressure conditions needs to be clarified. This paper discusses the mechanism of delamination of the intermediate layer of a DLC coating on a bearing in a test rig and by numerical simulation using FEM analysis. Test results revealed that the smaller the Young's modulus value of the intermediate layer (a factor affecting durability) of the DLC coating, the greater the resistance to delamination.

Temperate phages infect bacteria by injecting their DNA into bacterial cells, where it becomes incorporated into the host genome as a prophage. In the genome of Bacillus subtilis 168, an active prophage, SPβ, is inserted into a polysaccharide synthesis gene, spsM. Here, we show that a rearrangement occurs during sporulation to reconstitute a functional composite spsM gene by precise excision of SPβ from the chromosome. SPβ excision requires a putative site-specific recombinase, SprA, and an accessory protein, SprB. A minimized SPβ, where all the SPβ genes were deleted, except sprA and sprB, retained the SPβ excision activity during sporulation, demonstrating that sprA and sprB are necessary and sufficient for the excision. While expression of sprA was observed during vegetative growth, sprB was induced during sporulation and upon mitomycin C treatment, which triggers the phage lytic cycle. We also demonstrated that overexpression of sprB (but not of sprA) resulted in SPβ prophage excision without triggering the lytic cycle. These results suggest that sprB is the factor that controls the timing of phage excision. Furthermore, we provide evidence that spsM is essential for the addition of polysaccharides to the spore envelope. The presence of polysaccharides on the spore surface renders the spore hydrophilic in water. This property may be beneficial in allowing spores to disperse in natural environments via water flow. A similar rearrangement occurs in Bacillus amyloliquefaciens FZB42, where a SPβ-like element is excised during sporulation to reconstitute a polysaccharide synthesis gene, suggesting that this type of gene rearrangement is common in spore-forming bacteria because it can be spread by phage infection.

Background and study aims: The clinical utility of computed virtual chromoendoscopy with flexible spectral imaging color enhancement (FICE) in capsule endoscopy (CE) remains controversial. To clarify the clinical utility of FICE-enhanced CE in evaluating small bowel lesions, we quantitatively assessed white light (WL), FICE, and blue mode (BM) images and examined the sensitivity of these 3 imaging modes of small-bowel lesions from patients who underwent CE. Methods: The CIELAB color difference (∆E) and visual analogue scales (VAS) were measured in 261 CE images (3 different lesion categories) using WL and FICE set 1, 2, and 3, and BM images, respectively. Three endoscopists reviewed CE videos with WL, 3 FICE mode settings, and BM, and compared the sensitivity and detectability for small intestinal diseases from 50 patients who underwent CE. Results: In the assessment of visibility in the 152 vascular lesion images, the ∆E and VAS of FICE set 1, 2, and BM images were significantly higher than that of WL images. In 88 erosion/ulceration images, the ∆E and VAS of FICE set 1 and 2 images were significantly higher than that of WL images. In 21 tumor images, there were no significant differences in ∆E among these modalities. When analyzed on a per-patient basis, FICE settings 1 and 2 had the highest sensitivity (100 %) and specificity (97.3 – 100 %) for vascular lesions. As for erosive/ulcerative lesions, FICE setting 2 had the highest sensitivity (100 %) and specificity (97.2 %). For tumors or polyps, WL had the highest sensitivity (90.9 %) and specificity (87.1 %). In per-lesion analysis, FICE settings 1 and 2 showed significantly superior detection ability over WL for vascular lesions. In the detection of erosive/ulcerative lesions, FICE setting 2 was significantly superior to WL. In tumor images, there was no significant improvement with any of the settings relative to WL images. Conclusions: FICE is most useful for improving CE image quality and detection in cases of angioectasia and erosion/ulceration of the small intestine.

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.

Background We have previousy reported on a Phase II study of S-1 monotherapy as a first line, combination therapy of S-1 plus cisplatin as a second line, and weekly paclitaxel monotherapy as a third line therapy in patients with advanced gastric carcinomas. The median survival time (MST) of patients over the whole course of treatment was not previously calculated because 12 out of 19 patients had not yet succumbed. Since then, we have calculated the MST for this study and herein report our findings. Patients and Methods Between 2002 and 2005, 19 patients were enrolled in this study. Chemotherapy consisted of either 60 mg/m 2 of S-1 for 4 weeks at 6-week intervals, a combination of 60 mg/m 2 S-1 for 3 weeks and 60 mg/m 2 cisplatin on day 8 at 5-week intervals, or 60 mg/m 2 paclitaxel at days 1, 8, and 15, at 4-week intervals. The regimens were repeated until the occurrence of unacceptable toxicities, disease progression, or patient noncompliance. The primary end point was the overall survival. Results The median survival time was 774 days. The response rates were 33.3% (3/9), 12.5% (1/8), and 0% (0/4) after the first, second, and third line chemotherapies, respectively. The major adverse hematological toxicity was leukopenia, which reached grades 3–4 in all lines of chemotherapy investigated. In addition, the major adverse non-hematological toxicity was anorexia, which reached grade 3–4 in second line chemotherapy, and no deaths were attributable to the adverse effects of the drugs. Conclusion This sequential therapy was an effective treatment for advanced gastric cancer with acceptable toxic side-effects. We considered this therapy to be effective because of the smooth transition to the next regimen.

Background We conducted a pilot phase II study to evaluate the efficacy and safety of S-1 as a first-line, S-1 plus cisplatin as a second-line, and weekly paclitaxel as a third-line therapy for advanced gastric cancer. Patients and Methods Between 2002 and 2005, 19 patients were enrolled in this study. Chemotherapy consisted of either 60 mg/m 2 of S-1 for 4 weeks at 6 weeks interval, a combination of 60 mg/m 2 S-1 for 3 weeks and 60 mg/m 2 cisplatin on day 8 at 5 weeks interval, or 60 mg/m 2 paclitaxel at day 1, 8, 15, at 4 weeks interval. The regimen was repeated until the occurrence of unacceptable toxicities, disease progression, or patient refusal. The primary end point was the overall survival. Results The response rates were 33.3%, 12.5%, and 0% after the first, second, and third line chemotherapy, respectively. The mean overall survival time was 994 days. The median survival time could not be calculated because 12 out of 19 patients were still alive when the study was concluded. Regarding hematological toxicity, the major adverse effect was leukopenia, which reached grades 3–4 in all lines of chemotherapy investigated. In addition, regarding non-hematological toxicities, the major adverse effect was anorexia, which reached grade 3–4 in the second line chemotherapy, and no deaths were attributable to the adverse effects of the drugs. Conclusion This sequential therapy was an effective treatment for advanced gastric cancer with acceptable toxic side-effects. We considered this sequential therapy to be effective because of the smooth switch to the next regimen.

Asymmetric division during sporulation by Bacillus subtilis generates a mother cell that undergoes a 5-h program of differentiation. The program is governed by a hierarchical cascade consisting of the transcription factors: sigma(E), sigma(K), GerE, GerR, and SpoIIID. The program consists of the activation and repression of 383 genes. The sigma(E) factor turns on 262 genes, including those for GerR and SpoIIID. These DNA-binding proteins downregulate almost half of the genes in the sigma(E) regulon. In addition, SpoIIID turns on ten genes, including genes involved in the appearance of sigma(K). Next, sigma(K) activates 75 additional genes, including that for GerE. This DNA-binding protein, in turn, represses half of the genes that had been activated by sigma(K) while switching on a final set of 36 genes. Evidence is presented that repression and activation contribute to proper morphogenesis. The program of gene expression is driven forward by its hierarchical organization and by the repressive effects of the DNA-binding proteins. The logic of the program is that of a linked series of feed-forward loops, which generate successive pulses of gene transcription. Similar regulatory circuits could be a common feature of other systems of cellular differentiation.