Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2−Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2−Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra α-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2−Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasio

Comparison of standard versus 90° rotation technique for LMA Flexible™ insertion: a randomized controlled trial

Background Insertion of a flexible laryngeal mask airway (LMA Flexible) is known to be more difficult than that of a conventional laryngeal mask airway. The 90° rotation technique can improve the success rate with a conventional laryngeal mask airway but its effect with the LMA Flexible remains unknown. We assessed whether the 90° rotation technique increased the first-attempt success rate of LMA Flexible insertion versus the standard technique. Methods In total, 129 female patients undergoing breast surgery were analyzed. The primary endpoint was success at the first attempt. The insertion time, number of trials, number of manipulations required, and oropharyngeal leak pressure were also evaluated. Heart rate and mean blood pressure were recorded 1 min before and 1 min after insertion. Blood staining on the LMA Flexible after removal and postoperative sore throat were checked. Results The first-attempt success rates were comparable between the groups (93% vs. 98.3%, P = .20). The insertion time, number of trials and manipulations, hemodynamic variables, and complications, such as blood staining and sore throat, did not differ between the groups. Conclusions The 90° rotation technique is a good alternative to the standard technique for insertion of the LMA Flexible. Trial registration ClinicalTrials.gov(NCT03028896). It was registered retrospectively at Jan 19th, 2017.ASA: American Society of Anesthesiologists; BMI: Body mass index; IV: Intravenous; LMA: Laryngeal mask airway; MAP: Mean arterial pressure; NRS: Numerical rating scale; PACU: Post-anesthetic care unit; SD: Standard deviatio

Multimodality Imaging Can Help to Doubt, Diagnose and Follow-Up Cardiac Mass

Primary cardiac lymphoma is a very rare form of lymphoma primarily or mainly involving the heart, as in the two cases presented in this report. Various imaging modalities, including coronary computed tomography angiography, cardiac magnetic resonance imaging and positron emission tomography were useful for the characterization and diagnosis of cardiac mass. Pathologic confirmation was successful with endomyocardial biopsy under echocardiographic guidance, intra- and extracardiacally. In primary cardiac lymphoma, diagnosis using multiple modalities may be useful for mass characterization, and for response monitoring after chemotherapy

Efficacy of Abatacept Versus Tumor Necrosis Factor Inhibitors in Anti-citrullinated Protein Antibody-Positive Patients with Rheumatoid Arthritis: Results from a Korean Nationwide Biologics Registry

Abstract Introduction To compare the efficacy of abatacept and tumor necrosis factor inhibitor (TNFi) in patients with anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) and identify those who benefit most from abatacept over TNFi. Methods This observational study identified RA patients who were ACPA-positive and initiated abatacept or TNFi from the Korean College of Rheumatology Biologics and Targeted therapy registry. Propensity score (PS) matching was performed to balance baseline confounding in abatacept- or TNFi-treated patients. The major endpoints were changes in Clinical Disease Activity Index (CDAI) and achievement of CDAI remission/low disease activity after 1year of treatment. Subgroup analysis was mainly performed stratified by prior biologics use. Results A total of 291 PS-matched, ACPA-positive RA patients who initiated abatacept (n = 97) and TNFi (n = 194) were included. From baseline CDAI scores of 26.52 in the abatacept group and 26.38 in the TNFi group, the mean changes after 1year were − 16.78 and − 13.61, respectively (difference − 3.17, p = 0.020). The proportion of patients achieving CDAI remission/low disease activity was 68.0% with abatacept and 52.6% with TNFi (p = 0.013). In the subgroup analysis, patients that were biologics-naïve had better improvement in CDAI after treatment with abatacept than TNFi (difference −3.35, p = 0.021). Conclusions This real-world study suggests that abatacept may have better clinical response compared to TNFi in patients with established ACPA-positive RA, especially in those that were biologics-naïve

Second Primary Glioblastoma Multiforme Following Autologous Hematopoietic Stem Cell Transplantation in a Patient with Acute Myelogenous Leukemia

Glioblastoma multiforme (GM) is one of the most aggressive primary brain tumors, and has a poor prognosis despite intensive treatment. GM is also the most malignant astrocytoma, with histopathological features that include cellular polymorphism, rapid mitotic activity, microvascular proliferation, and necrosis. The causes of GM remain obscure, but several reports have shown associations between GM and genetic alterations and radiation exposure. Furthermore, high-dose chemotherapy/radiotherapy with autologous stem cell transplantation is increasingly being used to treat patients with leukemia, and patients who undergo stem cell transplantation have a higher risk of solid tumor cancer development later in life. Based on these associations, we discuss GM development in a patient who underwent chemoradiotherapy conditioning prior to stem cell transplantation

TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy

The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib.

Recent Trend in the Incidence of Premalignant and Malignant Skin Lesions in Korea between 1991 and 2006

We evaluated the recent trend in the incidence of premalignant and malignant skin lesions between 1991 and 2006. Among 571,057 newly registered dermatology out-patients from our 8 affiliated university hospitals, 2,598 were diagnosed with a premalignant (899, 0.16%) or malignant skin lesions (1,699, 0.30%). Of 899 premalignant cases, 71.2% were actinic keratosis (AK), and 24.6% were Bowen's disease. Of 1,699 malignant cases, 46.2% were basal cell carcinoma, followed by squamous cell carcinoma (19.1%) and melanoma (7.1%). This 16-yr survey was divided equally into two time periods to compare the incidence of premalignant and malignant skin lesions at different time settings. Between 1991 and 1998, the incidence of cutaneous premalignancy was 0.10% which doubled during 1999-2006. For cutaneous malignancy, the incidence was 0.25% during 1991-1998 and 0.34% in 1999-2006. Incidence of AK among the new outpatients was 0.07% in 1991-1998 which staggered up to 0.15% in 1999-2006. These findings show an increase of both premalignant and malignant skin lesions, AK in particular in the dermatology outpatient-based incidence

The Surgical Outcome of Endoscopic Dacryocystorhinostomy According to the Obstruction Levels of Lacrimal Drainage System

ObjectivesMany factors influence the outcome of endoscopic dacryocystorhinostomy (DCR). One of the most important prognostic factors is the level of obstruction in the lacrimal drainage system. The main objective of this report is to evaluate both the frequency of obstruction by anatomical region of the lacrimal drainage system on dacryocystography (DCG) and the surgical outcome of endoscopic DCR according to the obstruction level.MethodsA retrospective series of 48 patients (60 eyes) who had undergone endoscopic DCR from January 2005 to November 2007 were enrolled. Preoperative evaluation consisted of a standard examination which included lacrimal irrigation, probing, DCG and osteomeatal unit (OMU) computed tomography. Patients were classified into four groups according to the obstruction level on DCG. Surgical outcome was evaluated postoperatively by subjective improvement of epiphora and patent rhinostomy opening on nasal endoscopic exam.ResultsOf 60 eyes, the levels of obstruction were the common canaliculus in 14 eyes (23.3%), the lacrimal sac in 13 eyes (21.7%), the duct-sac junction in 13 eyes (21.7%) and the nasolacrimal duct (NLD) in 20 eyes (33.3%). The ductsac junction obstruction was treated most successfully (100%), followed by NLD obstruction (90%), common canaliculus obstruction (78.6%) and saccal obstruction (69.2%).ConclusionIn patients with lacrimal drainage system obstruction, preoperative evaluation of obstruction level using DCG may be helpful for predicting the surgical outcome of endoscopic DCR. The saccal obstruction may have a worse prognosis than the other obstruction levels

Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination

In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single-stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra ?-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle-like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion