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Anastomotic leakage (AL) following low anterior resection (LAR) for rectal cancer is a major complication. While most reports focus on the closure of AL using over-the-scope clip (OTSC), few reports are available on the use of through-the-scope clip (TTSC). This is because TTSC is not typically designed for full-thickness closure, unlike OTSC. However, a MANTIS clip, categorized as TTSC, is indicated for full-thickness closure. A 73-year-old man diagnosed with AL 7 days postoperatively following laparoscopic LAR underwent laparoscopic drainage and ileostomy the next day. Although the drainage led to the shrinkage of the fistula, it persisted even after 2 months. Consequently, the fistula orifice was closed using a MANTIS clip under colonoscopy and radiography. Two days later, the patient was discharged. The drain was withdrawn cautiously to prevent residual fistula and removed completely on day 29. This report highlights our experience in using a MANTIS clip for AL following LAR., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With the increase of the number of interventional radiology (IVR) procedures, the occupational exposure of operators and medical staff has attracted keen attention. The energy of scattered radiation in medical clinical sites is important for estimating the biological effects of occupational exposure. Recent years have seen many reports on the dose of scattered radiation by IVR, but few on the energy spectrum. In this study, the energy spectrum of scattered X-rays was measured by using a cadmium telluride (CdTe) semiconductor detector during IVR on several neurosurgical and cardiovascular cases. The cumulated spectra in each case were compared. The spectra showed little changes among neurosurgical cases and relatively large changes among cardiovascular cases. This was assumed to be due to the change of X-ray tube voltage and tube angle was larger in cardiovascular cases. The resulting energy spectra will be essential for the assessment of detailed biological effects of occupational exposure., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To analyse the microstructural changes of subchondral trabecular bone in patients with osteonecrosis of the femoral head (ONFH) using multi-detector row computed tomography (MDCT)., Methods: We retrospectively investigated 76 hips in 50 patients diagnosed with ONFH between 2017 and 2021. Groups 1, 2, 3, and 4 comprised hips without ONFH, ONFH without femoral head collapse (FHC), ONFH with mild collapse (<2 mm), and ONFH with severe collapse (>2 mm), respectively. All patients underwent MDCT, and the subchondral trabecular bone microstructure was assessed. Regions of interests were set at the lateral boundary of the femoral head necrotic lesion and centre of the acetabular weight-bearing portion., Results: In both the femoral head and the acetabular regions, there were significant differences in Groups 2 and 3 compared to Group 1, with increased volumetric bone mineral density and apparent bone volume fraction, and more plate-like with increased connectivity, indicating that osteosclerotic changes were occurring., Conclusions: In both the femoral head and the acetabular regions, osteosclerotic changes of subchondral trabecular bone microstructure were present before FHC., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Single-stranded RNA folds into a variety of secondary and higher-order structures. Distributions and dynamics of multiple RNA conformations are responsible for the biological function of RNA. We here developed a photoswitchable molecular glue for RNA, which could reversibly control the association of two unpaired RNA regions in response to light stimuli. The photoswitchable molecular glue, NCTA, is an RNA-binding ligand possessing a photoisomerizable azobenzene moiety. Z-NCTA is an active ligand for the target RNA containing 5'-WGG-3'/5'-WGG-3' (W = U or A) site and stabilizes its hybridized state, while its isomer E-NCTA is not. Photoreversible isomerization of NCTA enabled control of the secondary and tertiary structure of the target RNA. The RNA-cleaving activity of hammerhead ribozyme, where appropriate RNA folding is necessary, could be reversibly regulated by photoirradiation in cells treated with NCTA, demonstrating precise photocontrol of RNA structure and function by the photoswitchable molecular glue., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In June 2021, the Ministry of Health, Labor and Welfare approved Delytact Injection as a regenerative medical product for oncolytic virus therapy. The active substance of Delytact Injection is teserpaturev, a genetically engineered herpes simplex virus type 1 (strain F) in which the α47 gene and both copies of the γ34.5 gene have been deleted and the infected cell protein 6 (ICP6) gene has been inactivated by the insertion of the lacZ gene from Escherichia coli. Delytact Injection, when intratumorally administered to patients with malignant glioma, is expected to exert the following effects: (1) the mutant virus selectively replicates in tumor cells and destroys the infected cells through the replication process, exerting a cytocidal effect, and (2) the administration leads to induction of tumor-responsive T cells, which activates antitumor immunity and thus prolongs the survival of patients with malignant glioma. A Japanese phase II study (Study GD01) was conducted in patients with glioblastoma who had residual or recurrent tumors after radiotherapy with concomitant temozolomide. In Study GD01, however, stable disease continued for an extended period in some patients with glioblastoma. Hence, Delytact Injection is expected to be effective to a certain level. In line with this, Delytact Injection has been approved as an option for the treatment of malignant glioma, with one of the 3 approval conditions including conducting a use-results comparison survey and resubmission of the marketing authorization application within the granted time period of 7 years, under the conditional and time-limited approval scheme described in Article 23-26 of Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices., (© The Author(s) 2023. Published by Oxford University Press.)

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: No easy-to-use fall risk assessment tools have been devised to assess occupational fall risk in older workers., Aims: To develop an Occupational Fall Risk Assessment Tool (OFRAT) and report its predictive validity and reliability in older workers., Methods: The baseline fall risk assessment was completed by 1113 participants aged ≥60 years who worked ≥4 days/month in Saitama, Japan. Participants were followed up for falls during occupational activities for 1 year, and 30 participants were assessed twice for test-retest reliability. The following assessment measures were summed to form the OFRAT risk score: older age, male sex, history of falls, physical work participation, diabetes, use of medications increasing fall risk, reduced vision, poor hearing, executive dysfunction and slow stepping. The scores were then classified into four grades (0-2 points: very low, 3 points: low, 4 points: moderate and ≥5 points: high)., Results: During follow-up, 112 participants fell 214 times during work. The negative binomial regression model showed that participants with higher grades had a higher incidence rate ratio [95% confidence interval] for falls than those with very low grades (low: 1.64 [1.08-2.47], moderate: 4.23 [2.82-6.34] and high: 6.12 [3.83-9.76]). The intraclass correlation coefficient for risk score was 0.86 [0.72-0.93], and the weighted kappa coefficient for grade assessment was 0.74 [0.52-0.95]., Conclusions: The OFRAT is a valid and reliable tool for estimating the occupational fall risk in older workers. It may assist occupational physicians implement strategies to prevent falls in this group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer., Methods: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given., Results: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies., Conclusion: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347)., (Published by Oxford University Press 2022.)

Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder and rarely coexists with aortic aneurysms requiring open repair. A 66-year-old patient with MG underwent extended thoraco-abdominal aortic aneurysm (TAAA) repair 16 years after onset of type-B acute aortic dissection. At 62 years, the patient was diagnosed with MG (MGFA class IIIa) from positive anti-acetylcholine receptor antibody without thymoma. Preoperatively, MG was well-controlled by prednisolone, cyclosporin and pyridostigmine. Extent II TAAA repair was performed under general anaesthesia maintained by total intravenous anaesthesia. Transcranial motor-evoked potential and somatosensory-evoked potential were applied to monitor intraoperative spinal cord ischaemia and muscle weakness. Amplitudes of motor-evoked potential and somatosensory-evoked potential attenuated intraoperatively but normalized after reperfusion from the reconstructed tube graft. Perioperative steroid coverage was given against surgical stress. The patient was weaned from mechanical ventilatory support on postoperative day 7. No signs of spinal cord ischaemia or muscle weakness were seen., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Tanaidaceans are small benthic crustaceans that mainly inhabit diverse marine environments, and they comprise one of the most diverse and abundant macrofaunal groups in the deep sea. Tanaidacea is one of the most thread-dependent taxa in the Crustacea, constructing tubes, spun with their silk, for shelter. In this work, we sequenced and assembled the comprehensive transcriptome of 23 tanaidaceans encompassing 14 families and 4 superfamilies of Tanaidacea, and performed silk proteomics of Zeuxo ezoensis to search for its silk genes. As a result, we identified two families of silk proteins that are conserved across the four superfamilies. The long and repetitive nature of these silk genes resembles that of other silk-producing organisms, and the two families of proteins are similar in composition to silkworm and caddisworm fibroins, respectively. Moreover, the amino acid composition of the repetitive motifs of tanaidacean silk tends to be more hydrophilic, and therefore could be a useful resource in studying their unique adaptation of silk use in a marine environment. The availability of comprehensive transcriptome data in these taxa, coupled with proteomic evidence of their silk genes, will facilitate evolutionary and ecological studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

It was previously reported that oleanolic acid and ursolic acid, triterpenoid compounds occurring in Ilex kudingcha, ameliorate hyperlipidemia and atherosclerosis in apoE-deficient mice. In the present study, we investigated whether I. kudingcha extract exerts similar inhibitory effects on cholesterol accumulation in human monocyte-derived macrophages (HMDMs) and atherogenesis in apoE-deficient mice. I. kudingcha extract significantly inhibited cholesterol ester (CE) accumulation induced by acetylated LDL (acetyl-LDL) in HMDMs; however, it generated no effect on cell viability in HMDMs. I. kudingcha extract also suppressed CE accumulation in acyl-CoA:cholesterol acyl-transferase (ACAT)-overexpressing Chinese hamster ovary (CHO) cells, thereby indicating that it inhibits ACAT activity. Furthermore, the oral administration of I. kudingcha extract to apoE-deficient mice significantly decreased the levels of serum cholesterol, triglyceride, sLOX-1, as well as the regions of atherosclerotic lesions in the mice. Our study reveals crucial new-found evidence that I. kudingcha extract significantly inhibits ACAT activity and suppresses atherogenesis., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly., Methods: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared., Results: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor., Conclusion: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Dietary fatty acids can affect chronic intestinal inflammation and have been reported to be associated with the development of ulcerative colitis (UC), mainly in Europe and the United States. The association of dietary intake of fatty acids and the risk for UC was investigated in Japan, where dietary habits lead to lower meat and higher fish consumption than in Western countries., Methods: A multicenter case-control study of 83 newly diagnosed patients with UC and 128 age- and sex-matched control patients in the hospital was conducted from 2008 to 2014. Dietary fatty acid intake in the preceding 1 month and 1 year were examined using a self-administered diet history questionnaire that was developed for Japanese people., Results: About 92% of patients had experienced the first symptoms of UC within the preceding 11 months. Regarding dietary habits in the preceding year, the risk for UC was significantly decreased in patients who consumed n-6/n-3 polyunsaturated fatty acids at a ratio of ≥5.2 (odds ratio [OR] = 0.26; 95% confidence interval [CI], 0.10-0.68). Conversely, an increased risk for UC was observed in the highest tertiles of consumption of docosahexaenoic acid (OR = 7.22; 95% CI, 2.09-24.95), eicosapentaenoic acid (OR = 6.91; 95% CI, 1.88-25.44), and docosapentaenoic acid (OR = 4.83; 95% CI, 1.56-14.95)., Conclusions: The ratio of n-6/n-3 polyunsaturated fatty acid intake was associated with a decreased risk for UC development. However, high intakes of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid may increase the risk for UC development., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This review introduces the definition, epidemiology and therapeutic challenges of rare cancers and describes the establishment of the Rare Cancer Center at the National Cancer Center, Japan. Rare cancers are defined as malignant tumors with an incidence rate of less than 6 cases per 100 000 individuals. Due to their low incidence rate, medical treatment for rare cancers is more challenging than for more common cancer types. Specifically, 190 types of cancers, including bone and soft tissue sarcomas, gastrointestinal stromal tumors (GISTs), neuroendocrine tumors and gliomas, are classified as rare cancers. Individually, each of the rare cancers accounts for less than 1% of all cancers, but collectively they account for 15% of all cancers. On the basis of their medical management, rare cancers can be subclassified into two types: Type I (rare cancers within cancer-rare organs) and Type II (rare cancers within cancer-common organs). Most importantly, the outcomes for rare cancers are poorer compared to those of common cancers. In 2014, the Rare Cancer Center was established at the National Cancer Center to address the various challenges related to rare cancers. The Rare Cancer Center has adopted a multifaceted approach for overcoming these challenges, including active sharing of information through a dedicated website and an online seminar series 'Rare Cancer Meet the Expert', providing medical support through telephone consultations via a 'Rare Cancer Hotline', supporting basic research and establishing the 'MASTER KEY Project' aimed at developing new treatments., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types., Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor-β (TGF-β) RII receptor (a TGF-β "trap") fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death-ligand 1 (PD-L1). Bintrafusp alfa is designed to neutralize TGF-β signaling by "trapping" and sequestering all TGF-β isoforms, and this trap function is physically linked to PD-L1 blockade in the tumor microenvironment., Methods: NCT02699515 was a phase I, open-label, dose-escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety-assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response., Results: As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment-related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment-related deaths occurred. In the dose-escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose-proportional pharmacokinetics profile was observed at doses of >3 mg/kg., Conclusion: Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

The precise mechanisms of the reproductive physiological processes, such as labor initiation, are poorly understood. Oxytocin (OT) is one of the well-known uterotonics and is clinically adopted as a medication to facilitate childbirth. Vasopressin (VP), a posterior pituitary hormone similar to OT, has also been proposed to be involved in the reproductive physiology. In this study, we found that a total deficiency of V1a receptor subtype (V1aR) in mice resulted in a reduced number of pups, delayed labor initiation, and increased post-delivery hemorrhage compared with those in wild-type mice. Among the VP receptor subtypes, only V1aR was found to be expressed in the murine uterus, and its distribution pattern was different from that of the oxytocin receptor (OTR); V1aR expression was mainly distributed in the circular myometrium, whereas OTR was strongly expressed in both the circular and longitudinal myometrium. The maximum contractile force of the circular myometrium, induced by VP or OT, was attenuated in the pregnant uterus of Avpr1a-deficient mice. Contrarily, while OT expression was decreased in the Avpr1a-deficient uterus, OTR expression was significantly increased. These results suggest that V1aR deficiency not only reduces the uterine contractile force but also perturbs the expression of genes responsible for the reproductive physiology. Therefore, V1aR is necessary to exert the maximum contraction of the circular myometrium to deliver pups. This study revealed an important role of V1aR in physiological contraction and term parturition in mice., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Optimal cancer survivorship care needs its comprehensive guidelines. We aimed to identify English and Japanese guidelines that include cancer survivorship in their title, the issues highlighted in such guidelines, and any existing oncology practice guidelines in Japan that address these issues., Methods: This literature review was performed in three stages. First, guidelines published in English or Japanese that included cancer survivorship in the title were identified. Then, the issues that each cancer survivorship guideline addressed were defined. Lastly, Japanese guidelines that include survivorship issues were sought., Results: Six guidelines published in English addressed 31 cancer survivorship issues. No specific cancer survivorship guideline was available in Japanese. Thirty-four Japanese guidelines mentioned cancer survivorship issues. These guidelines addressed screening/surveillance for detecting recurrence or secondary cancer but did not address coordination of care, implications for practice, or inclusion of family. At present, Japanese guidelines poorly address the issue of promotion of a healthy lifestyle in cancer survivors. Also, poorly addressed were long-term and late effects such as pain, psychological distress, fatigue, cognitive dysfunction, cardiovascular effects (including anthracycline-induced cardiac toxicity), sleep disorders, and sexual dysfunction in cancer survivors., Conclusion: There is a need for guidelines on optimal coordination of care between oncologists and other health care providers to support patients along the cancer care continuum and specifically to encourage a healthy lifestyle as part of cancer survivorship. The development of a comprehensive Japanese guideline that addresses these issues would help to improve the clinical outcome for cancer survivors in Japan., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening cutaneous and mucosal adverse reactions to drugs. Nevertheless, the connection to anticancer agents remains unclear. To provide insight into the association of such adverse reactions with anticancer agents, we analyzed the profile of anticancer agent-induced SJS and TEN in the Japanese population. Of the 9,738 SJS/TEN events recorded in a database of spontaneous reporting data, 485 (5%, further categorized as SJS, 384 events, 79%; TEN, 101 events, 21%) were identified as anticancer agent-induced, and 53 of these (11%) were fatal. Multivariate logistic regression analyses indicated that, compared with patients using other drugs, those using anticancer drugs had lower incident risk of death (hazard ratio [HR], 0.592; p  = .0006), longer median time to onset of SJS/TEN (18 vs. 11 days; p  < .0001; multivariate Cox regression: HR, 0.66; p  < .0001), and a higher likelihood of developing SJS/TEN later than 70 days after initiation of the suspected causal agent (15% vs. 7%; p  < .0001), highlighting the need for vigilance and continuous monitoring for SJS/TEN in patients treated with anticancer agents. IMPLICATIONS FOR PRACTICE: Life-threatening skin toxicities induced by anti-cancer agents indicated significantly lower incident risk of death and longer time to onset of symptoms than for those induced by other drugs., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Little is known about the prevalence and pathogenicity of human herpes viruses except for cytomegalovirus (CMV) in patients with inflammatory bowel disease (IBD). The aim of this study was to determine the prevalence of human herpes viruses on colonic mucosa in patients with IBD and assess the long-term outcomes in these patients., Methods: We examined the colonic mucosal specimens from 66 patients with ulcerative colitis (UC), 54 patients with Crohn's disease (CD), and 29 healthy patients to identify the 6 most common types of human herpes virus, using multiplex polymerase chain reaction (PCR) technique., Results: Herpes simplex virus (HSV)-1/2 and varicella-zoster virus (VZV) were not detected in any of the groups. There was a higher prevalence of Epstein-Barr virus (EBV) (21.2%) and CMV (15.1%) in patients with UC than in patients with CD (EBV 9.3%, CMV 0%) and patents in the healthy control group (EBV 0%, CMV 3.4%). The prevalence of human herpes virus (HHV)-6A/B and HHV-7 was not statistically different among the groups. Five UC patients with inflammation had coexisting CMV and EBV or HHV-6. The combined infection of CMV with EBV or HHV-6 was a significant and independent prognostic factor for subsequent colectomy in patients with UC., Conclusions: The increased prevalence of CMV coexisting with EBV/HHV-6 infection was associated with the clinical course in patients with UC. 10.1093/ibd/izy005&#95;video1izy005&#95;Video&#95;15786489376001.

Background and Aims: Novel noninvasive biomarkers with high diagnostic accuracy are required to assess mucosal healing, which is associated with sustained clinical remission, in inflammatory bowel disease. This study aimed to explore sepsis markers as potential biomarkers for mucosal healing., Methods: Patients with ulcerative colitis [UC] or Crohn's disease [CD], who underwent blood tests for C-reactive protein [CRP], serum procalcitonin [PCT], soluble interleukin-2 receptor [sIL-2R], and plasma soluble CD14 subtype [sCD14-ST] within 2 weeks of endoscopy, were retrospectively recruited; and we assessed the relationship between marker levels and clinical features. Complete mucosal healing [cMH] was defined as a Mayo endoscopic subscore [MES] of 0 for UC and a simple endoscopic score for Crohn's disease [SES-CD] of 0 for CD., Results: In all, 68 UC patients and 33 CD patients were included in this study. In patients with UC, the sIL-2R level was significantly higher in patients without cMH than in those with cMH. The sIL-2R level had the highest diagnostic value for identifying cMH in UC. In patients with CD, CRP and sCD14-ST levels were significantly higher in patients without cMH than in those with cMH, and both CRP and sCD14-ST had good diagnostic values for identifying cMH. The sCD14-ST level had a high diagnostic value for identifying cMH even among CD patients with complete clinical remission, defined as a Harvey-Bradshaw index of 0., Conclusions: The sIL-2R and sCD14-ST levels in patients with UC and CD, respectively, can be useful surrogate markers for identifying mucosal healing in inflammatory bowel disease., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: The standard treatment for limited-disease small-cell lung cancer (LD-SCLC) is a combination of chemotherapy and concurrent thoracic radiotherapy. In selected cases, sequential radiotherapy is preferred because of the need for a large irradiation field, patient age, comorbidities or performance status. Nevertheless, the efficacy of sequential chemoradiotherapy in patients in whom concurrent chemoradiotherapy is contraindicated is not well known., Methods: We retrospectively analyzed 286 patients with LD-SCLC at two institutions in Japan between 2000 and 2014. We compared the clinical characteristics and treatment outcomes of patients undergoing sequential radiotherapy with those undergoing concurrent radiotherapy., Results: One hundred and seventy-five patients received concurrent chemoradiotherapy, 33 received sequential chemoradiotherapy and 46 received chemotherapy only. The median patient age was 64 years (range, 18-82 years) for the concurrent group and 71 years (49-82 years) for the sequential group. Conventional radiotherapy was selected more frequently than accelerated hyperfractionated radiotherapy (27 patients [82%] with conventional radiotherapy, and six patients [18%] with hyperfractionated radiotherapy). The major reasons for the selection of sequential radiotherapy were advanced age (12 patients) and a large irradiation field (11 patients). The median overall survival time was 41.1 months for the sequential group and 38.1 months for the concurrent group. The 5-year survival rates were 36.0% for the sequential group and 41.6% for the concurrent group., Conclusions: In clinical situation, since the treatment outcomes for patients with sequential radiotherapy were comparable to those receiving concurrent radiotherapy, sequential chemoradiotherapy can be a choice for the treatment of patients who are not candidates for concurrent chemoradiotherapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg kd ) in which Erg expression can be conditionally restored by Cre recombinase. Erg kd/kd animals die at E10.5-E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Erg kd/+ mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin - Sca-1 + c-Kit + (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Erg kd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. Stem Cells 2017;35:1773-1785., (© 2017 AlphaMed Press.)

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan., Methods: Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital. We examined the efficacy and safety of osimertinib in a compassionate use program., Results: All patients had been previously treated with both cytotoxic chemotherapy and EGFR TKIs. Overall response rate was 62.5% (95% confidence interval (CI): 35.9-89.1%). Among the six patients pretreated with a third-generation EGFR TKI, two (33%) responded to osimertinib. On administration with osimertinib, median progression-free and overall survival rates at six months were 66.7% (95% CI: 44.9-88.5) and 88.9% (95% CI: 74.4-100), respectively. Although the toxicity of osimertinib was mild in most patients, three patients had severe adverse events: two developed interstitial lung disease (ILD) and one developed Grade 3 hepatotoxicity. Among these, two (33%) of the six patients who received osimertinib following nivolumab treatment developed severe adverse events, with one each developing Grade 3 hepatotoxicity and Grade 3 ILD. Only one patient visited our hospital seeking to participate in the compassionate program from another hospital., Conclusion: Osimertinib demonstrated efficacy even in patients with heavily pretreated NSCLC harboring the T790M mutation. Some patients pretreated with another third-generation EGFR TKI also responded to osimertinib., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Cell metabolism can be considered as a process of serial construction and destruction of cellular components, both of which must be regulated accurately. In eukaryotic cells, a variety of cellular components are actively delivered into lysosomes/vacuoles, specialized compartments for hydrolysis of macromolecules. Such processes of 'self-eating' are called autophagy. Despite a wide variety of lysosomal/vacuolar hydrolases, much of the interest has been focused on the proteolytic functions of autophagy and less attention has been devoted to the degradation of other macromolecules such as nucleic acids. In this review, we focus on delivery and degradation of endogenous nucleic acids by autophagic systems, and discuss their molecular mechanisms and physiological/pathophysiological roles., (© The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors., Methods: The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method., Results: Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively., Conclusion: In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy., Implications for Practice: Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors., (©AlphaMed Press.)

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although the mechanisms of this association have not been fully elucidated, nighttime reflux plays a central role. However, the detailed characteristics of nighttime reflux occurring during sleep are unknown. The aim of the present study was to examine the characteristics and prevalence of nighttime reflux in the natural sleep environment of GERD patients. Seventeen patients experiencing daily moderate-to-severe heartburn and/or regurgitation were studied using multichannel intraluminal impedance pH monitoring and electroencephalography off-proton pump inhibitor treatment. Nighttime reflux was divided based on reflux type (liquid or gas), acidity (acidic, weakly acidic, or alkaline) and extent (distal only or proximal migration) according to the standard criteria. Nighttime phases were divided as follows: recumbent-awake before falling asleep, nonrapid eye movement, rapid eye movement, awakening from sleep, and post-awakening in the morning. Among 184 nighttime refluxes, 43 (23%) occurred during recumbent-awake before falling asleep, 28 (15%) during nonrapid eye movement, 14 (8%) during rapid eye movement, 86 (46%) during awakening from sleep, and 13 (7%) during post-awakening in the morning. Liquid reflux was more common in awakening during sleep (92%), nonrapid eye movement (100%), and rapid eye movement (100%) compared with awakening before falling asleep (68%). The prevalence of proximal migration was significantly lower in nonrapid eye movement and rapid eye movement than in the other phases. There were no differences in acidity and bolus clearance time among the phases. Thirteen (65%) of 20 events with GERD symptoms had nighttime reflux, suggesting that only 7.1% (13 of 184) of nighttime refluxes were symptomatic. Nighttime reflux was observed in 48 (11%) of 425 awakening episodes during sleep. Different reflux patterns at each phase during nighttime might explain the pathogenesis of GERD and its related sleep disturbances., (© 2015 International Society for Diseases of the Esophagus.)

Purpose: The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC)., Experimental Design: Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues., Results: cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (+) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKI-sensitive and T790M mutations, respectively. Next-generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance., Conclusion: Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs., Implications for Practice: Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors., (©AlphaMed Press.)

Objective: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer., Methods: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate., Results: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia., Conclusions: While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lysosomes can degrade various biological macromolecules, including nucleic acids, proteins and lipids. Recently, we identified novel nucleic acid-degradation systems termed RNautophagy/DNautophagy (abbreviated as RDA), in which RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded. We also found that a lysosomal membrane protein, LAMP2C, the cytoplasmic region of which binds to RNA and DNA, functions, at least in part, as an RNA/DNA receptor in the process of RDA. However, it has been unclear whether RDA possesses selectivity for RNA/DNA substrates and the RNA/DNA sequences that are recognized by LAMP2C have not been determined. In the present study, we found that the cytosolic region of LAMP2C binds to poly-G/dG, but not to poly-A/dA, poly-C/dC, poly-dT or poly-U. Consistent with this binding activity, poly-G/dG was transported into isolated lysosomes via RDA, while poly-A/dA, poly-C/dC, poly-dT and poly-U were not. GGGGGG or d(GGGG) sequences are essential for the interaction between poly-G/dG and LAMP2C. In addition to poly-G/dG, G/dG-rich sequences, such as a repeated GGGGCC sequence, interacted with the cytosolic region of LAMP2C. Our findings indicate that RDA does possess selectivity for RNA/DNA substrates and that at least some consecutive G/dG sequence(s) can mediate RDA., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The cholesterol ester accumulates in macrophages in the early stage of atherosclerotic lesions, leading to the formation of foam cells. We examined the inhibitory effects of the crude extracts of 22 edible plants on foam cell formation and isolated nine chlorophyll derivatives as potent inhibitors from Chinese cabbage. The results of the present study suggest that the chlorophyll derivatives contained in edible plants may be useful for the prevention and treatment of atherosclerosis.

Objective: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients., Methods: Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method., Results: This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose., Conclusions: Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The effects of dietary soybean β-conglycinin on lipid metabolism and energy consumption were studied in Wistar adult rats. Rats were fed, a diet containing casein (control group) or β-conglycinin (β-conglycinin group), for 4 weeks. Carbohydrate consumption was higher and fat consumption was lower in the β-conglycinin group than in the control group, whereas the total energy consumption was the same between the two groups. Serum adiponectin was higher in the β-conglycinin group than in the control group. Serum triacylglycerol levels in the β-conglycinin group were significantly lower than those in the control group. The secretion rate of triacylglycerols from the liver after the administration of tyloxapol, an inhibitor of lipolysis, was significantly lower in the β-conglycinin group than in the control group. These results suggest the possibility that β-conglycinin exerts hypolipidemic effects through an acceleration in carbohydrate consumption associated with an increase in adiponectin in rats.

Objective: Several clinical studies have demonstrated the efficacy and safety of adjuvant chemotherapy in patients with completely resected small cell lung cancer for a selected limited stage. However, it is unclear whether adjuvant chemotherapy is feasible in clinical practice. The objective of this study was to analyze the efficacy and safety of adjuvant chemotherapy for small cell lung cancer patients retrospectively in clinical practice., Methods: From January 2002 to March 2012, 56 small cell lung cancer patients underwent surgery as initial therapy in our institute. Of these, 26 patients received adjuvant chemotherapy. The clinical data of patients who received adjuvant chemotherapy were retrospectively analyzed., Results: The chemotherapy regimens were cisplatin and irinotecan in 16 patients, cisplatin and etoposide in 1 and carboplatin and etoposide in 9. Median follow-up time was 44.8 months. Nineteen (73%) patients received the full course of chemotherapy. Median recurrence-free survival was 21.4 months. Median survival time was not reached. There was no treatment-related death., Conclusion: Adjuvant chemotherapy may be generally safe and efficacious in selected small cell lung cancer patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Aims: Appropriate influenza vaccination is important for patients with inflammatory bowel disease under immunosuppressive therapy. The purpose of this study was to evaluate the influence of immunosuppressive therapy on the immune response to the trivalent influenza vaccine in adult patients with inflammatory bowel disease., Methods: In this cohort study, 91 participants received a single dose of influenza vaccine for the 2010/2011 season. Serum samples were collected at 3 different times (pre-vaccination, 3 weeks post-vaccination, and after flu season) to measure hemagglutination inhibition antibody titers. Immune responses were compared based on immunosuppressive therapy., Results: Among the 88 subjects who completed the study, the influenza vaccine induced a more than 4-fold increase in the mean antibody level for all flu strains. The overall seroprotection proportion (post-vaccination titer ≥ 1:40) was 81% for H1N1, 61% for H3N2, and 86% for B. Treatment with an immunomodulator reduced the immune response to the H1N1 strain (OR=0.20, p=0.01), and treatment with infliximab reduced the immune response to the other strains (H3N2 strain: OR=0.37, p=0.02; B strain: OR=0.18, p=0.03). Combination therapy with azathioprine/6-mercaptopurine and infliximab significantly inhibited the immune response to H1N1 (OR=0.056, p=0.02)., Conclusions: Infliximab and/or immunomodulators inhibit immune responses to some strains of trivalent influenza vaccination in adults with inflammatory bowel disease. For optimization of the trivalent influenza vaccination for patients with adult inflammatory bowel disease treated with immunosuppressive agents, establishing an effective vaccination method is crucial., (© 2013.)

A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor.

With the use of a mouse FDC line, FL-Y, we have been analyzing roles for FDCs in controlling B cell fate in GCs. Beside these regulatory functions, we fortuitously found that FL-Y cells induced a new type of CD11b⁺ monocytic cells (F4/80⁺, Gr-1⁻, Ly6C⁻, I-A/E(-/lo), CD11c⁻, CD115⁺, CXCR4⁺, CCR2⁺, CX₃CR1⁻) when cultured with a Lin⁻c-kit⁺ population from mouse spleen cells. The developed CD11b⁺ cells shared a similar gene-expression profile to mononuclear phagocytes and were designated as FDMCs. Here, we describe characteristic immunological functions and the induction mechanism of FDMCs. Proliferation of anti-CD40 antibody-stimulated B cells was markedly accelerated in the presence of FDMCs. In addition, the FDMC-activated B cells efficiently acquired GC B cell-associated markers (Fas and GL-7). We observed an increase of FDMC-like cells in mice after immunization. On the other hand, FL-Y cells were found to produce CSF-1 as well as IL-34, both of which are known to induce development of macrophages and monocytes by binding to the common receptor, CSF-1R, expressed on the progenitors. However, we show that FL-Y-derived IL-34, but not CSF-1, was selectively responsible for FDMC generation using neutralizing antibodies and RNAi. We also confirmed that FDMC generation was strictly dependent on CSF-1R. To our knowledge, a CSF-1R-mediated differentiation process that is intrinsically specific for IL-34 has not been reported. Our results provide new insights into understanding the diversity of IL-34 and CSF-1 signaling pathways through CSF-1R.

Lipid droplets (LDs) are independent organelles in adipocytes that are composed of a lipid ester core surrounded by a phospholipid monolayer. The fatty acid composition of the phospholipid monolayer should determine the metabolism and dynamics of LDs. In this study, we examined the fatty acid composition of phospholipid monolayer in LDs during the differentiation of 3T3-L1 adipocytes. The levels of saturated fatty acids (SFAs), such as 16:0 and 18:0, in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of LDs decreased during differentiation. In contrast, the levels of monounsaturated fatty acids (MUFAs) such as 16:1n-7 and 18:1n-9 in PC and PE of LDs and the level of polyunsaturated fatty acids (PUFAs) such as 20:3n-6, 20:4n-6 and 22:6n-3 in PE of LDs increased during differentiation. These results suggest that the phospholipid monolayer in mature LDs is more fluid than that in nascent LDs. The fatty acid compositions of the LD monolayer were different from those of the microsome bilayer in the early stage of differentiation, but similar to those of the microsome bilayer in the late stage of differentiation. These data provide evidence that biophysical properties of the phospholipid monolayer in LDs change during adipocyte differentiation.

Syntaxin2 (STX2), also known as epimorphin, is a member of the SNARE family of proteins, with expression in various types of cells. We previously identified an ENU-induced mutation, repro34, in the mouse Stx2 gene. The Stx2(repro34) mutation causes male-restricted infertility due to syncytial multinucleation of spermatogenic cells during meiotic prophase. A similar phenotype is also observed in mice with targeted inactivation of Stx2, as well as in mice lacking enzymes involved in sulfoglycolipid synthesis. Herein we analyzed expression and subcellular localization of STX2 and sulfoglycolipids in spermatogenesis. The STX2 protein localizes to the cytoplasm of germ cells at the late pachytene stage. It is found in a distinct subcellular pattern, presumably in the Golgi apparatus of pachytene/diplotene spermatocytes. Sulfoglycolipids are produced in the Golgi apparatus and transported to the plasma membrane. In Stx2(repro34) mutants, sulfoglycolipids are aberrantly localized in both pachytene/diplotene spermatocytes and in multinucleated germ cells. These results suggest that STX2 plays roles in transport and/or subcellular distribution of sulfoglycolipids. STX2 function in the Golgi apparatus and sulfoglycolipids may be essential for maintenance of the constriction between neighboring developing spermatocytes, which ensures ultimate individualization of germ cells in later stages of spermatogenesis.

Overexpression of LIN28A is associated with human germ cell tumors and promotes primordial germ cell (PGC) development from embryonic stem cells in vitro and in chimeric mice. Knockdown of Lin28a inhibits PGC development in vitro, but how constitutional Lin28a deficiency affects the mammalian reproductive system in vivo remains unknown. Here, we generated Lin28a knockout (KO) mice and found that Lin28a deficiency compromises the size of the germ cell pool in both males and females by affecting PGC proliferation during embryogenesis. Interestingly however, in Lin28a KO males, the germ cell pool partially recovers during postnatal expansion, while fertility remains impaired in both males and females mated to wild-type mice. Embryonic overexpression of let-7, a microRNA negatively regulated by Lin28a, reduces the germ cell pool, corroborating the role of the Lin28a/let-7 axis in regulating the germ lineage., (Copyright © 2013 AlphaMed Press.)

We report the case of a 49-year-old non-smoking Japanese woman with backache and difficulty in walking. She was diagnosed as having advanced lung adenocarcinoma, and an epithelial growth factor receptor mutation (in-frame deletions in exon 19) was found. After radiation therapy of bone metastases with spinal cord compression and brain metastases, gefitinib was administered. On day 2, she developed acute interstitial lung disease. Gefitinib therapy was discontinued and treatment with high-dose steroid therapy improved the interstitial lung disease. Cisplatin plus pemetrexed was initiated as second-line chemotherapy, but she was hospitalized again for leptomeningeal carcinomatosis. Considering the poor prognosis of leptomeningeal carcinomatosis, we decided that erlotinib was our only choice of treatment. As a third-line treatment, erlotinib was administered after informing the patient about the high risk of interstitial lung disease. Neurological symptoms were improved within a week and interstitial lung disease did not recur. The patient has received erlotinib successfully for 18 months without the recurrence of leptomeningeal carcinomatosis. Erlotinib rechallenge after gefitinib-induced interstitial lung disease must be carefully chosen based on the balance of a patient's risk and benefit.

Background: Assessment of renal function is important for safe cancer chemotherapy, and eligibility criteria for clinical trials often include creatinine clearance. However, creatinine clearance overestimates glomerular filtration rate, and various new formulae have been proposed to estimate glomerular filtration rate. Because these were developed mostly in patients with chronic kidney disease, we evaluated their validity in cancer patients without kidney disease., Methods: Glomerular filtration rate was measured by inulin clearance in 45 Japanese cancer patients, and compared with creatinine clearance measured by 24-h urine collection as well as that estimated by the Cockcroft-Gault formula, Japanese estimated glomerular filtration rate developed in chronic kidney disease patients, the Modification of Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration equation. The Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration equations were adjusted for the Japanese population by multiplying by 0.808 and 0.813, respectively., Results: The mean inulin clearance was 79.2 ± 18.7 ml/min/1.73 m(2). Bias values to estimate glomerular filtration rate for Japanese estimated glomerular filtration rate, the Cockcroft-Gault formula, creatinine clearance measured by 24-h urine collection, the 0.808 × Modification of Diet in Renal Disease study equation and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation were 0.94, 9.75, 29.67, 5.26 and -0.92 ml/min/1.73 m(2), respectively. Precision (root-mean square error) was 14.7, 22.4, 39.8, 16.0 and 14.1 ml/min, respectively. Of the scatter plots of inulin clearance versus each estimation formula, the Japanese estimated glomerular filtration rate correlated most accurately with actual measured inulin clearance., Conclusion: The Japanese estimated glomerular filtration rate and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation estimated glomerular filtration rate with lower bias and higher precision than the other formulae. We therefore propose Japanese estimated glomerular filtration rate for the estimation of glomerular filtration rate in Japanese cancer patients.

Hydrothermal vents are typically located in midocean ridges and back-arc basins and are usually generated by the movement of tectonic plates. Life thrives in these environments despite the extreme conditions. In addition to chemoautotrophic bacteria, decapod crustaceans are dominant in many of the hydrothermal vents discovered to date. Contrary to the hypothesis that these species are remnants of relic fauna, increasing evidence supports the notion that hydrothermal vent decapods have diversified in more recent times with previous research attributing the origin of alvinocarid shrimps to the Miocene. This study investigated seven representative decapod species from four hydrothermal vents throughout the Western Pacific and Indian Oceans. A partitioned mix-model phylogenomic analysis of mitochondrial DNA produced a consistent phylogenetic topology of these vent-endemic species. Additionally, molecular dating analysis calibrated using multiple fossils suggested that both bythograeid crabs and alvinocarid shrimps originated in the late Mesozoic and early Cenozoic. Although of limited sampling, our estimates support the extinction/repopulation hypothesis, which postulates recent diversification times for most hydrothermal vent species due to their mass extinction by global deep-water anoxic/dysoxic events during the Late Cretaceous and Early Tertiary. The continental-derived property of the West Pacific province is compatible with the possibility that vent decapods diversified from ancestors from shallow-water regions such as cold seeps. Our results move us a step closer toward understanding the evolutionary origin of hydrothermal vent species and their distribution in the Western Pacific-Indian Ocean Region.

Resveratrol (RSV), 3,5,4'-trihydroxy-trans-stilbene, is known to have many beneficial physiological activities. We have synthesized several stilbene analogues and have reported that the hydroxyl group in the 4' position of RSV exhibited strong radical scavenging action. Using stilbene analogs, we investigated the structure of RSV to explain its protective effect against obesity and type 2 diabetes. All six analogs used in this study inhibited the differentiation of 3T3-L1 adipocytes. 3-Hydroxy-trans stilbene (3(OH)ST), and 3,4'-dihydroxy-trans stilbene (3,4'(OH)2ST) increased glucose uptake and induced adenosine monophosphate kinase (AMPK) phosphorylation in C2C12 myotubes independently of insulin. An in vivo study using mice fed high-fat diets indicated that 3(OH)ST was more effective than RSV in improving insulin resistance. In conclusion, RSV and its derivatives, particularly 3(OH)ST, inhibited adipocyte differentiation and enhanced glucose uptake in the myotubes, resulting in a reduction of obesity and an improvement in glucose tolerance in vivo.