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NADH:ubiquinone oxidoreductase (complex I) plays a central role in the respiratory electron transport chain by coupling the transfer of electrons from NADH to ubiquinone to the creation of the proton gradient across the membrane necessary for ATP synthesis. Here the atomistic details of electronic wiring of all Fe/S clusters in complex I are revealed by using the tunneling current theory and computer simulations; both density functional theory and semiempirical electronic structure methods were used to examine anti-ferromagnetically coupled spin states and corresponding tunneling wave functions. Distinct electron tunneling pathways between neighboring Fe/S clusters are identified; the pathways primarily consist of two cysteine ligands and one additional key residue. Internal water between protein subunits is identified as an essential mediator enhancing the overall electron transfer rate by almost three orders of magnitude to achieve a physiologically significant value. The identified key residues are further characterized by sensitivity of electron transfer rates to their mutations, examined in simulations, and their conservation among complex I homologues. The unusual electronic structure properties of Fe₄S₄ clusters in complex I explain their remarkable efficiency of electron transfer.

In Japan, 1.5–2 million people are chronically infected with hepatitis C virus (HCV) infection. New direct-acting antiviral agents (DAA) offer an unprecedented opportunity to cure HCV. While the price of HCV treatment decreased recently in most countries, it remains one of the highest in Japan. Our objective was to evaluate the cost-effectiveness of HCV treatment in patients of different age groups and to estimate the price at which DAAs become cost-saving in Japan. A previously developed microsimulation model was adapted to the Japanese population and updated with Japan-specific health utilities and costs. Our model showed that compared with no treatment, the incremental cost-effectiveness ratio (ICER) of DAAs at a price USD 41,046 per treatment was USD 9,080 per quality-adjusted life year (QALY) gained in 60-year-old patients. HCV treatment became cost-effective after 9 years of starting treatment. However, if the price of DAAs is reduced by 55–85% (USD 6,730 to 17,720), HCV treatment would be cost-saving within a 5 to 20-year time horizon, which should serve to increase the uptake of DAA-based HCV treatment. The payers of health care in Japan could examine ways to procure DAAs at a price where they would be cost-saving.

Cancer stem cells (CSCs) play an essential role in tumorigenesis, chemoresistance, and metastasis. Previously, we demonstrated that the development of hepatocellular carcinoma (HCC) is dictated by a subset of epithelial cell adhesion molecule-positive (EpCAM+) liver CSCs with the activation of Wnt signaling. In this study, we evaluated the expression of dUTP pyrophosphatase (dUTPase), which plays a central role in the development of chemoresistance to 5-fluorouracil, in EpCAM+ HCC cells. We further evaluated the effect of beta-hydroxyisovaleryl-shikonin (β-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases, on HCC CSCs. EpCAM and dUTPase were expressed in hepatoblasts in human fetal liver, hepatic progenitors in adult cirrhotic liver, and a subset of HCC cells. Sorted EpCAM+ CSCs from HCC cell lines showed abundant nuclear accumulation of dUTPase compared with EpCAM-negative cells. Furthermore, treatment with the Wnt signaling activator BIO increased EpCAM and dUTPase expression. In contrast, β-HIVS treatment decreased dUTPase expression. β-HIVS treatment decreased the population of EpCAM+ liver CSCs in a dose-dependent manner in vitro and suppressed tumor growth in vivo compared with the control vehicle. Taken together, our data suggest that dUTPase could be a good target to eradicate liver CSCs resistant to 5-fluorouracil. β-HIVS is a small molecule that could decrease dUTPase expression and target EpCAM+ liver CSCs.

Pancreatic ductal adenocarcinoma (PDAC) is the most life‐threating disease among all digestive system malignancies. We developed a blood mRNA PDAC screening system using real‐time detection PCR to detect the expression of 56 genes, to discriminate PDAC from noncancer subjects. We undertook a clinical study to assess the performance of the developed system. We collected whole blood RNA from 53 PDAC patients, 102 noncancer subjects, 22 patients with chronic pancreatitis, and 23 patients with intraductal papillary mucinous neoplasms in a per protocol analysis. The sensitivity of the system for PDAC diagnosis was 73.6% (95% confidence interval, 59.7%‐84.7%). The specificity for noncancer volunteers, chronic pancreatitis, and patients with intraductal papillary mucinous neoplasms was 64.7% (54.6%‐73.9%), 63.6% (40.7%‐82.8%), and 47.8% (26.8%‐69.4%), respectively. Importantly, the sensitivity of this system for both stage I and stage II PDAC was 78.6% (57.1%‐100%), suggesting that detection of PDAC by the system is not dependent on the stage of PDAC. These results indicated that the screening system, relying on assessment of changes in mRNA expression in blood cells, is a viable alternative screening strategy for PDAC. Development of a blood mRNA pancreatic ductal adenocarcinoma (PDAC) screening system using real‐time detection PCR in order to discriminate PDAC patients from healthy volunteers. We performed an investigator‐initiated clinical study to assess the performance of the developed system. The sensitivity of the system for PDAC diagnosis and the specificity for non‐cancer volunteers were determined for the evaluation of the screening system.

Background Reuse of injection devices to give healthcare injections decreased from 39.8 to 5.5% between 2000 and 2010, but trends since 2011 have not been described. We reviewed results of Demographic and Health Surveys (DHS) to describe injection practices worldwide from 2011 to 2015. Methods We searched the DHS Internet site for data published on injection practices conducted in countries from 2011 to 2015, extracted information on frequency (number of healthcare injections per person in the last 12 months) and safety (proportion of syringes and needles taken from a new, unopened package). We compared gender groups and WHO regions in terms of frequency and safety. For countries with data available, we compared injection practices 2004–2010 and 2011–2015. Results Since 2011, 40 of 92 countries (43%) that conducted DHS surveys reported on injection practices. On average, the frequency of injection was 1.64 per person per year (from 3.84 in WHO Eastern Mediterranean region to 1.18 in WHO African region). Among those, 96.1% of injections reportedly used new injection devices (from 90.2% in the WHO Eastern Mediterranean region to 98.8% in the WHO Western Pacific region). On average, women received more injections per year (1.85) than men (1.41). Among 16 (40%) countries with data in 2004–2010 and 2011–2015, 69% improved in terms of safety. The annual number of unsafe injections reduced in 81% of countries. In Pakistan, the number of unsafe injections was the highest and did not decrease between 2006 and 2012. Conclusions Injection practices have continued to improve in most countries worldwide, although the Eastern Mediterranean region in particular still faces unsafe practices that are not improving. Further efforts are needed to eliminate unsafe injection practices in health care settings, including through the use of reuse-prevention devices. Despite some limitations, DHS is an easily available method to measure progress over time.

This study aimed to evaluate the efficacy of a novel fully covered self-expandable metal stent (SEMS) with dumbbell-shaped flare ends for the palliation of distal biliary obstruction (DBO) due to unresectable pancreatic cancer (UPC). Patients with DBO due to UPC who received the novel HILZO fully covered stent (HFS), the WALLFLEX partially covered stent (WPS) or fully covered stent (WFS) were analyzed. The incidence of recurrent biliary obstruction (RBO), time to RBO (TRBO), and the incidence of complications were compared among the three SEMS groups. Eighty-four patients (HFS, n  = 36; WPS, n  = 20; WFS, n  = 28) were included. The incidence of RBO was low in the HFS group (versus the WPS and WFS group, p  = 0.033 and 0.023, respectively). TRBO in the HFS group was longer than that in the WFS group ( p  = 0.049). Placement of the HFS was an independent factor for long TRBO in multivariable analysis ( p  = 0.040). The incidence of pancreatitis and cholecystitis in the HFS group was low (one for each). It is recommended to use the HFS for the palliation of DBO due to UPC from the viewpoint of the low incidence of RBO and complications.

Background Salvage photodynamic therapy with talaporfin sodium has a high local control rate for esophageal cancer after definitive chemoradiotherapy. The eligibility criteria for photodynamic therapy include the absence of invasion to the cervical esophagus and a 3 cm maximum longitudinal lesion length. There is little evidence regarding the efficacy and safety of lesions outside the eligibility criteria. This retrospective cohort study evaluated the efficacy and safety of photodynamic therapy of such lesions. Methods Patients with consecutive lesions between February 2016 and May 2020 ( n  = 36) were enrolled. The local complete response rates and adverse events were compared between patients with cervical and non-cervical lesions and those with lesions larger and smaller than 3 cm. Results The local complete response rate was 77.8% and was significantly lower in cervical than in non-cervical lesions (20.0% vs 80.6%, p  = 0.005). Esophageal stricture, laryngeal pain, and fever were significantly higher in the cervical than in the non-cervical lesion group; however, the detected adverse events were up to grade 2. Laser exposure dose was high in lesions larger than 3 cm (median, 650 vs 400 J; p  < 0.001). No significant differences in local complete response rates and adverse effects were noted. One case involving a lesion larger than 3 cm needed balloon dilations for esophageal stricture. Conclusions Although salvage esophageal photodynamic therapy was effective for local control with acceptable safety after definitive chemoradiotherapy failure, photodynamic therapy toward cervical lesions had a statistically lower local complete response rate. Lesions larger than 3 cm may be considered treatable.

Glioblastoma is one of the most aggressive brain tumors in adults. The standard treatment is radiotherapy and chemotherapy based on the Stupp regimen after maximal safe resection. One effective chemotherapeutic drug is bevacizumab, which can prolong progression-free survival in glioblastoma patients but not overall survival. Adverse events of bevacizumab include hypertension, proteinuria, delayed wound healing, bleeding of the nose and gums, and thromboembolism resulting in gastrointestinal perforation. Herein, we describe an autopsy case of a patient with glioblastoma who died from non-occlusive mesenteric ischemia that was presumably caused by bevacizumab.

Cancer stem cells (CSCs) are a pivotal target for eradicating hepatocellular carcinoma (HCC). We previously reported that distinctive CSCs regulating tumorigenicity (EpCAM + CSCs) and metastasis (CD90 + CSCs) have different epithelial/mesenchymal gene expression signatures. Here, we examined the influence of sorafenib, a multiple-receptor tyrosine kinase inhibitor used as a first-line treatment for advanced HCC, on EpCAM + and CD90 + CSCs. CD90 + cells showed higher c-Kit gene/protein expression than EpCAM + cells. Sorafenib treatment reduced the number of CD90 + cells with attenuated c-Kit phosphorylation, whereas it enriched the EpCAM + cell population. We evaluated the role of CD90 + and EpCAM + CSCs in vivo by subcutaneously injecting these CSCs together in immune-deficient mice. We observed that sorafenib subtly affected the suppression of primary tumor growth maintained by EpCAM + CSCs, but completely inhibited the lung metastasis mediated by CD90 + CSCs. We further evaluated the effect of sorafenib on extracellular vesicle (EV) production and found that sorafenib suppressed the production of EVs containing TGF-β mRNA in CD90 + cells and inhibited the cell-cell communication and motility of EpCAM + cells. Our data suggest the following novel effects of sorafenib: suppressing CD90 + CSCs and inhibiting the production of EVs regulating distant metastasis.

Mint3 enhances aerobic ATP production with subsequent nuclear translocation of hypoxia-inducible factor-1 (HIF-1) and activation of angiogenesis-related genes. It remains unclear if and when Mint3 is activated and whether it is involved in hepatocarcinogenesis. We explored the expression of Mint3 in surgically resected hepatocellular carcinoma (HCC) tissues. We evaluated the effects of Mint3 knockdown on spheroid formation capacity and subcutaneous tumor growth in immune-deficient mice. We used Mint3 knockout mice to evaluate the effects of chemically induced HCC development. Mint3 was overexpressed in well-differentiated HCC with the activation of HIF-1 target genes irrespective of the absence of hypervascularization. Mint3 knockdown ameliorated the expression of HIF-1 target genes in patient-derived HCC cell lines and suppressed spheroid formation. Mint3 knockdown further inhibited subcutaneous tumor formation in vivo in immune-deficient mice. Chemical HCC development induced by N-nitrosodiethylamine (DEN) or DEN/CCl4 was dramatically suppressed in Mint3 knockout mice compared to control mice. Mint3 plays a crucial role in early-stage HCC development before hypervascularization by activating HIF-1 target genes before the tumor becomes hypoxic. Mint3 is a molecular target that prevents HCC development in the early stages.