The use of non-surgical glue to repair perineal first-degree lacerations in normal birth: A non-inferiority randomised trial.

BACKGROUND AND PROBLEM: Surgical glue has been indicated for uncomplicated operatory wounds; however, it has a considerable cost. Non-surgical glue, a commercially available and cheaper product, has not been studied for repairing postpartum lacerations. AIM: To compare non-surgical glue to traditional sutures on perineal first-degree lacerations after normal birth. METHODS: In a prospective, open-label, non-inferiority, randomised controlled trial, we selected childbearing women who were admitted for normal term births and in whom skin lacerations occurred. They were assigned to laceration repair using either non-surgical glue (ethyl 2-cyanoacrylate; Glue group) or catgut sutures (Suture group). The primary endpoint was the occurrence of dehiscence >3mm. Secondary endpoints were procedure runtime, pain score, satisfaction level, and aspects of perineal repair by the REEDA score (hyperaemia, oedema, ecchymosis, exudation, and coaptation) immediately (T0), 24-48h (T1), and 7-10 days (T2) after childbirth. FINDINGS: We included 126 women, 63 in each group, and found a non-inferiority dehiscence rate in the Glue Group compared to the Control group (T1=1.6% vs. 1.6%, P=0.999 and P<0.001 for non-inferiority; and T2=2.2% vs. 4.3%, P=0.557). In the Glue Group, the procedure runtime was shorter, pain score was lower, and women's satisfaction was greater. No women had any allergic reaction in the study. CONCLUSIONS: Non-surgical glue was not inferior to traditional sutures to repair postpartum first-degree lacerations. In addition, non-surgical glue was associated with less pain and greater satisfaction. Brazilian Clinical Trials Registry (www.ensaiosclinicos.gov.br/rg/RBR-5Z8MKC).

Correction: Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prevalence and risk factors of zygotic splitting after 937 848 single embryo transfer cycles.

STUDY QUESTION: What is the prevalence of multiple pregnancy with zygotic splitting after single embryo transfer (SET)? SUMMARY ANSWER: The prevalence of multiple pregnancy with zygotic splitting after SET was 1.36%. WHAT IS KNOWN ALREADY: In 2008, the Japan Society of Obstetrics and Gynaecology (JSOG) recommended the adoption of SET to reduce multiple births. Since then, to improve the clinical pregnancy rate, elective SET using blastocyst transfer and frozen-warmed ET has increased. Blastocyst culture and zona pellucida manipulation, including ICSI and AH, have been widely reported as risk factors for monozygotic twinning. However, all these studies may have included cases with dizygotic pregnancies produced by a transferred embryo and a spontaneous conception. STUDY DESIGN, SIZE, DURATION: A retrospective observational study was performed, based on 937 848 SET cycles in registered ART data from the JSOG between 2007 and 2014. The study was approved by the Registration and Research Subcommittee of the JSOG and Juntendo University Ethics Committee. PARTICIPANTS/MATERIALS, SETTING, METHODS: To identify possible factors affecting the prevalence of zygotic splitting, we identified pregnancies, in which the number of foetuses exceeded the number of gestational sacs (GSs), to restrict our analysis to 'true' zygotic splitting. Multiple logistic regression analysis was performed using singleton pregnancy after SET, as control. P < 0.05 was considered statistically significant. MAIN RESULTS AND THE ROLE OF CHANCE: Fresh and frozen-warmed SET produced 276 934 clinical pregnancies (29.5%/SET), including 4310 twins (1.56% of pregnancies) and 109 triplets (0.04% of pregnancies). Based on sex analysis of dichorionic twins after SET, the prevalence of multiple pregnancy with zygotic splitting was 1.36%. Statistical analysis revealed that compared to singleton pregnancies zygotic splitting pregnancies were associated with frozen-warmed ET cycles (odds ratio [OR] = 1.34; 95% CI: 1.16-1.55), blastocyst culture (OR = 1.79; 95% CI: 1.54-2.09) or AH (OR = 1.21; 95% CI: 1.08-1.35). In fresh ET cycles, the prevalence rate of zygotic splitting pregnancy after single blastocyst transfer was significantly higher than that after SET cycles with cleavage embryos (OR = 2.20; 95% CI: 1.83-2.66). However, no significant difference in ovarian stimulation and fertilization methods was recognized. LIMITATIONS, REASONS FOR CAUTION: In the current Japanese ART registry system, data regarding frozen-warmed ET do not include information about ovarian stimulation and fertilization methods. Registration for AH only began in 2010. There is no way of validating if data submitted by clinics is correct. WIDER IMPLICATIONS OF THE FINDINGS: Clinicians should consider whether to counsel couples about the small increase in the risk of zygotic splitting associated with some embryo manipulations. STUDY FUNDING/COMPETING INTEREST(S): No external funds were used for the study. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: None.

Discovery of superconductivity in quasicrystal.

Superconductivity is ubiquitous as evidenced by the observation in many crystals including carrier-doped oxides and diamond. Amorphous solids are no exception. However, it remains to be discovered in quasicrystals, in which atoms are ordered over long distances but not in a periodically repeating arrangement. Here we report electrical resistivity, magnetization, and specific-heat measurements of Al-Zn-Mg quasicrystal, presenting convincing evidence for the emergence of bulk superconductivity at a very low transition temperature of [Formula: see text] K. We also find superconductivity in its approximant crystals, structures that are periodic, but that are very similar to quasicrystals. These observations demonstrate that the effective interaction between electrons remains attractive under variation of the atomic arrangement from periodic to quasiperiodic one. The discovery of the superconducting quasicrystal, in which the fractal geometry interplays with superconductivity, opens the door to a new type of superconductivity, fractal superconductivity.

Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.

Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcΔ716 Trp53LSL•R270H villin-CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcΔ716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcΔ716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcΔ716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs.

Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer.

BACKGROUND: In advanced gastric cancer (AGC), most clinical trials are designed on the basis of protein expression or gene amplification of specific genes. Recently, next-generation sequencing (NGS) allowed us to comprehensively profile the tumor gene status. This study aimed to elucidate the profiling between gene alterations and protein expression in AGC to aid in future clinical trials on AGC. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tumor samples from 121 stage III/IV gastric cancer patients were examined for protein expression of tyrosine kinase receptors (RTKs; ERBB2, EGFR, c-MET, and FGFR2) using immunohistochemistry (IHC). Furthermore, 409 cancer-related genes were sequenced to detect mutations and copy number variations using NGS. RESULTS: Most ERBB2 overexpression (IHC 3+) cases (80.0%) had ERBB2 amplification and did not have other RTK amplification or oncogene mutations. However, one-fourth of MET overexpression cases (25.0%) had ERBB2 alterations. EGFR and FGFR2 overexpression cases had ERBB2 alterations or other gene alterations such as KRAS or PIK3CA. On the other hand, most of the four RTK amplification cases (88.2%) were mutually exclusive with each amplification. However, RTK amplification did not simply correlate with protein overexpression, whereas cases with RTK high-level amplification had protein overexpression and rarely showed other co-existing gene alterations. CONCLUSION: AGC involves a complicated arrangement of protein expression and gene alterations. Comprehensive analyses of NGS and IHC will be necessary to design the optimal therapy for treating the appropriate population of patients in future clinical trials.

Frequent MED12 mutations in phyllodes tumours of the breast.

BACKGROUND: Phyllodes tumours are rare fibroepithelial tumours of the breast, that include benign, borderline, and malignant lesions. Although the molecular basis of phyllodes tumours largely remains unknown, a recent exome study identified MED12 mutations as a sole recurrent genetic alteration in fibroadenoma, a common benign fibroepithelial tumour that shares some histological features with the phyllodes tumour. METHODS: Forty-six phyllodes tumours and 58 fibroadenomas of the breast were analysed for MED12 mutations by using Sanger sequencing. RESULTS: MED12 mutations were identified in 37 out of the 46 phyllodes tumours (80%). The prevalence of MED12 mutations was similar among benign (15/18, 83%), borderline (12/15, 80%), and malignant tumours (10/13, 77%). MED12 mutations were also identified in 36 of the 58 fibroadenomas (62%). The mutations were frequent among intracanalicular-type (24/32, 75%) and complex-type lesions (4/6, 67%), but were significantly less common among the pericanalicular-type lesions (8/20, 40%). A microdissection-based analysis showed that MED12 mutations were confined to the stromal components in both phyllodes tumours and fibroadenomas. CONCLUSIONS: MED12 mutations were frequent among the phyllodes tumours of the breast, regardless of the tumour grade. Phyllodes tumours and fibroadenomas share, at least in part, a common genetic background.

α-Amylase is a potential growth inhibitor of Porphyromonas gingivalis, a periodontal pathogenic bacterium.

BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis is a major etiological agent in the development and progression of periodontal diseases. In this study, we isolated a cell growth inhibitor against P. gingivalis species from rice protein extract. MATERIAL AND METHODS: The cell growth inhibitor active against P. gingivalis was purified from polished rice extract using a six-step column chromatography process. Its antimicrobial properties were investigated through microscope analysis, spectrum of activity and general structure. RESULTS: The inhibitor was identified as AmyI-1, an α-amylase, and showed significant cell growth inhibitory activity against P. gingivalis species. Scanning electron microscopy micrograph analysis and bactericidal assay indicated an intriguing possibility that the inhibitor compromises the cell membrane structure of the bacterial cells and leads to cell death. Moreover, α-amylases from human saliva and porcine pancreas showed inhibitory activity similar to that of AmyI-1. CONCLUSIONS: This is the first study to report that α-amylases cause cell death of periodontal pathogenic bacteria. This finding highlights the potential importance and therapeutic potential of α-amylases in treating periodontal diseases.

Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer.

We built an in-house oligonucleotide array on which 394 genes were selected based on our Serial Analysis of Gene Expression (SAGE) data and previously reported array data and listed several genes related to cancer progression. Among these, we focused on SEC11A, which encodes the SPC18 protein. SEC11A mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in gastric cancer (GC) tissue samples. Expression and distribution of SPC18 protein were investigated by immunohistochemical analysis in two independent GC cohorts (Hiroshima cohort, n=99 and Chiba cohort, n=989). To determine the effect of SPC18 on cell viability and invasiveness in vitro, MTT and Boyden chamber invasion assays were performed. To evaluate the influence of SPC18 on cell growth in vivo, GC cells were injected into severe combined immunodeficiency mice. Levels of TGF-α and EGF in media from the GC cells were measured by enzyme-linked immunosorbent assay (ELISA). Studies in human tissue revealed overexpression of SEC11A mRNA in 40% of 42 GC samples by qRT-PCR. Immunohistochemical analysis of SPC18 revealed that 26 and 20% of GC cases were SPC18-positive in the Hiroshima and Chiba cohorts, respectively. In both cohorts, the Kaplan-Meier analysis showed poorer survival in SPC18-positive GC cases than in SPC18-negative GC cases. Forced expression of SPC18 activates GC cell growth in vitro and in vivo. The levels of TGF-α in culture media from GC cells were reduced by knockdown of SPC18. These results indicate that SPC18 contributes to malignant progression through promotion of TGF-α secretion in GC.

Distinct outcome of stage I lung adenocarcinoma with ACTN4 cell motility gene amplification.

BACKGROUND: Even if detected at an early stage, a substantial number of lung cancers relapse after curative surgery. However, no method for distinguishing such tumors has yet been established. PATIENTS AND METHODS: The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridization on tissue microarrays comprising 543 surgically resected adenocarcinomas of the lung. RESULTS: Amplification (an increase in the copy number by ≥ 2.0 fold) of the ACTN4 gene was detected in two of seven lung adenocarcinoma cell lines and 79 (15%) of 543 cases of pathological stage I-IV lung adenocarcinoma. Multivariate analysis revealed that ACTN4 gene amplification was the most significant independent factor associated with an extremely high risk of death (hazard ratio, 6.78; P = 9.48 × 10(-5), Cox regression analysis) among 290 patients with stage I lung adenocarcinoma. The prognostic significance of ACTN gene amplification was further validated in three independent cohorts totaling 1033 patients. CONCLUSIONS: Amplification of the ACTN4 gene defines a small but substantial subset of patients with stage I lung adenocarcinoma showing a distinct outcome. Such patients require intensive medical attention and might benefit from postoperative adjuvant chemotherapy.

Serum levels of IL-6 and IL-1ß can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer.

BACKGROUND: With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC). METHODS: Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively. RESULTS: Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1ß levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1ß level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1ß. CONCLUSION: The serum levels of IL-6 and IL-1ß predict the efficacy of GEM in patients with advanced PC.

KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer.

BACKGROUND: KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations. METHODS: A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated. RESULTS: The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions. CONCLUSION: Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.

KRAS mutations detected by the amplification refractory mutation system-Scorpion assays strongly correlate with therapeutic effect of cetuximab.

BACKGROUND: We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment. PATIENTS AND METHODS: We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system-Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S. RESULTS: Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001). CONCLUSION: Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.

MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes.

EZH2 overexpression occurs in various malignancies and is associated with a poor outcome. We have so far demonstrated that EZH2 downregulates the important genes such as E-cadherin and RUNX3 by increasing histone H3K27 trimethylation. However, the mechanism of EZH2 overexpression in various cancer cells remains unclear. In this study we carried out a promoter analysis of the EZH2 gene and investigated whether a survival signal that is upregulated in cancer cells is related to overexpression at the transcription level. We also explored the clinical relevance of the signaling pathway that leads to EZH2 overexpression in breast cancer and demonstrated that MEK-ERK1/2-Elk-1 pathway leads to EZH2 overexpression. The triple-negative and ERBB2-overexpressing subtypes of breast cancer are known to contain more rapidly proliferating breast cancer cells. The signaling pathway connected to EZH2 overexpression was associated with both aggressive subtypes of breast cancer. We show the significance that overexpression of histone modifier protein EZH2 in cancer cells and our study could pave the way for EZH2 inhibition to become an efficient treatment for more aggressive breast cancers.

Clinical impact of intraoperative histological examination of the ductal resection margin in extrahepatic cholangiocarcinoma.

BACKGROUND: Although ductal resection margin status in extrahepatic cholangiocarcinoma is evaluated by intraoperative histological examination of frozen sections, its clinical relevance remains controversial. METHODS: Material taken from patients who underwent R0 or R1 resection for extrahepatic cholangiocarcinoma with intraoperative histological examination of the final ductal resection margins between 1994 and 2003 were reviewed. The following histological classification was used: insufficient, negative for malignancy (NM), undetermined lesion (UDL) or positive for malignancy (PM). Multivariable analyses of overall survival and anastomotic recurrence in relation to ductal margin status were performed. RESULTS: Resection material from 363 patients was identified. For the proximal ductal margin, only PM in intramural lesions was significantly associated with poor survival (hazard ratio (HR) 1.72, 95 per cent confidence interval (c.i.) 1.06 to 2.74) and anastomotic recurrence (HR 6.39, 95 per cent c.i. 1.89 to 21.62) compared with NM. In analysis of overall survival according to distal ductal margin status, the HRs for UDL and PM lesions in comparison with NM were not significant. CONCLUSION: PM in intramural lesions found during intraoperative histological examination of the proximal ductal resection margin was related to clinical outcome. This finding favours additional resection of the bile duct. A similar association was not found for histology results of the distal resection margin.

Reduction of type II taste cells correlates with taste dysfunction after X-ray irradiation in mice.

BACKGROUND: Taste dysfunction that develops after radiotherapy for head and neck cancer impairs patients' quality of life. Although taste cells have been shown to degenerate after exposure to X-ray irradiation, the alteration in taste cell population is unclear. This study investigated the histopathological change of taste bud structure and the taste cell population in X-ray irradiated mice. METHODS: The head and neck region of C57BL/6J male mice was exposed to a single 15 Gy dose of X-ray irradiation and a chronological histopathological analysis of the circumvallate papilla was performed. Preference for sweet taste was measured using the two-bottle preference method. RESULTS: The histological analysis of the circumvallate papilla revealed that the basal cells had almost disappeared, but that there was not clear change in the spindle-shaped taste cells on day 4 after irradiation. The number of taste cells had decreased on day 8, and then remained unchanged until day 20, after which they increased and recovered to their original number by day 24. There was a more marked decrease in the number of alpha-gustducin-positive type II taste cells than in the number of serotonin-positive type III taste cells. Preference for sweet taste measured by the two-bottle preference method was decreased in parallel with taste cell number. CONCLUSION: These findings suggest that X-ray irradiation disrupts the basal cells, resulting in a decrease of the number of taste cells, particularly type II taste cells, which may be the cause of radiotherapy-induced taste dysfunction.

Pressure tuning of an ionic insulator into a heavy electron metal: an infrared study of YbS.

Optical conductivity [sigma(omega)] of YbS has been measured under pressure up to 20 GPa. Below 8 GPa, sigma(omega) is low since YbS is an insulator with an energy gap between a fully occupied 4f state and an unoccupied conduction (c) band. Above 8 GPa, however, sigma(omega) increases dramatically, developing a Drude component due to heavy carriers and characteristic infrared peaks. It is shown that increasing pressure has caused an energy overlap and hybridization between the c band and 4f state, thus driving the initially ionic and insulating YbS into a correlated metal with heavy carriers.

Association between ED and LUTS in Japanese motorcyclists.

Recently, the association between motorcycling and erectile dysfunction (ED) has been reported. Also, lower urinary tract symptoms (LUTS) were reported to be associated with ED. The aim of this study is to evaluate the association of ED with LUTS in motorcyclists. We investigated the prevalence and the status of ED using a 5-item version of the International Index of Erectile Function (IIEF-5) in 150 motorcyclists. ED was diagnosed when the IIEF-5 score was less than 17. The International Prostate Symptom Score (IPSS) was also applied, and the relationship between IIEF-5 and IPSS was evaluated. Of the 150 motorcyclists, 37 (25%) had ED, and 31 (21%) had moderate or severe symptoms of LUTS (IPSS >or=8). The IIEF-5 was significantly associated with the severity of IPSS (P=0.002) and age (P<0.0001). The IIEF-5 was also significantly associated with the scores of both voiding (P<0.0001) and storage symptoms (P=0.001). On stepwise logistic regression analysis, age and storage symptoms are independent risk factors for ED in motorcyclists. LUTS seemed to be associated with ED in motorcyclists.